{"id":4824,"date":"2023-03-16T11:26:16","date_gmt":"2023-03-16T03:26:16","guid":{"rendered":"http:\/\/dh.oncolab.cn\/index.php\/2023\/03\/16\/monthly-updates-2023-01\/"},"modified":"2025-01-03T18:49:39","modified_gmt":"2025-01-03T10:49:39","slug":"monthly-updates-2023-01","status":"publish","type":"post","link":"http:\/\/dh.oncolab.cn\/index.php\/2023\/03\/16\/monthly-updates-2023-01\/","title":{"rendered":"Monthly Updates 2023.01"},"content":{"rendered":"
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01<\/strong><\/p>\n<\/section>\n<\/section>\n

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01 J Hepatol. 20230125<\/strong><\/p>\n<\/section>\n<\/section>\n

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Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy<\/strong><\/p>\n

\u809d\u764c\u5fae\u73af\u5883\u4e2d\u5b58\u5728\u53ef\u51b3\u5b9a\u514d\u75ab\u6cbb\u7597\u6548\u679c\u7684\u80bf\u7624\u514d\u75ab\u5c4f\u969c<\/strong><\/span><\/p>\n


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J Hepatol. 2023 Jan 25;S0168-8278(23)00023-5. <\/em><\/p>\n

doi: <\/strong>10.1016\/j.jhep.2023.01.011.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36708811\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Background & aims:<\/strong> The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy. However, the specific structure of the TME and its role in immunotherapy efficacy remain largely unknown.<\/p>\n

\u80bf\u7624\u5fae\u73af\u5883(TME)\u662f\u5f71\u54cd\u80bf\u7624\u8fdb\u5c55\u548c\u6cbb\u7597\u6548\u679c\u7684\u5173\u952e\u56e0\u7d20\u3002\u5728\u591a\u79cd\u764c\u75c7\u4e2d\uff0cTME\u4e9a\u578b\u4e0e\u60a3\u8005\u5bf9\u514d\u75ab\u6cbb\u7597\u7684\u53cd\u5e94\u76f8\u5173\u3002\u4ee5\u5f80\u7684\u7814\u7a76\u5927\u591a\u96c6\u4e2d\u5728\u4e0d\u540c\u7ec6\u80de\u6210\u5206\u5728\u4e0e\u514d\u75ab\u6cbb\u7597\u7597\u6548\u76f8\u5173\u7684TME\u4e2d\u7684\u4f5c\u7528\u3002\u7136\u800c\uff0cTME\u7684\u5177\u4f53\u7ed3\u6784\u53ca\u5176\u5728\u514d\u75ab\u6cbb\u7597\u7597\u6548\u4e2d\u7684\u4f5c\u7528\u5c1a\u4e0d\u6e05\u695a\u3002<\/p>\n

Methods:<\/strong> We combined spatial transcriptomics with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the TME that determine the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 treatment.<\/p>\n

\u6211\u4eec\u5c06\u7a7a\u95f4\u8f6c\u5f55\u7ec4\u5b66\u4e0e\u5355\u7ec6\u80deRNA\u6d4b\u5e8f\u548c\u591a\u91cd\u514d\u75ab\u8367\u5149\u76f8\u7ed3\u5408\uff0c\u4ee5\u786e\u5b9a\u5728\u63a5\u53d7\u6297PD-1\u6cbb\u7597\u7684\u809d\u7ec6\u80de\u764c(HCC)\u60a3\u8005TME\u4e2d\u51b3\u5b9a\u514d\u75ab\u6cbb\u7597\u7597\u6548\u7684\u7279\u5b9a\u7a7a\u95f4\u7ed3\u6784\u3002<\/p>\n

Results:<\/strong> We identified a tumour immune barrier (TIB) structure, a spatial niche composed of SPP1+ macrophages and cancer-associated fibroblasts (CAFs) located near the tumour boundary, which is associated with the efficacy of immune checkpoint blockade. Furthermore, we dissected ligand\u2012receptor networks among malignant cells, SPP1+ macrophages, and CAFs; that is, the hypoxic microenvironment promotes SPP1 expression, and SPP1+ macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thereby limiting immune infiltration in the tumour core. Preclinically, the blockade of SPP1 or macrophage-specific deletion of Spp1 in mice led to enhanced efficacy of anti-PD-1 treatment in mouse liver cancer, accompanied by reduced CAF infiltration and increased cytotoxic T-cell infiltration.<\/p>\n

\u6211\u4eec\u53d1\u73b0\u4e86\u80bf\u7624\u514d\u75ab\u5c4f\u969c(TIB)\u7ed3\u6784\uff0c\u8fd9\u662f\u4e00\u4e2a\u7531\u4f4d\u4e8e\u80bf\u7624\u8fb9\u754c\u9644\u8fd1\u7684SPP1+\u5de8\u566c\u7ec6\u80de\u548c\u764c\u75c7\u76f8\u5173\u6210\u7ea4\u7ef4\u7ec6\u80de(CAFs)\u7ec4\u6210\u7684\u7a7a\u95f4\u9f9b\uff0c\u4e0e\u514d\u75ab\u68c0\u67e5\u70b9\u963b\u65ad\u7684\u7597\u6548\u76f8\u5173\u3002\u6b64\u5916\uff0c\u6211\u4eec\u5256\u6790\u4e86\u6076\u6027\u7ec6\u80de\u3001SPP1+\u5de8\u566c\u7ec6\u80de\u548cCAFs\u4e4b\u95f4\u7684\u914d\u4f53-\u53d7\u4f53\u7f51\u7edc\uff0c\u53d1\u73b0\u4f4e\u6c27\u5fae\u73af\u5883\u4fc3\u8fdbSPP1\u8868\u8fbe\uff0c\u4e14SPP1+\u5de8\u566c\u7ec6\u80de\u4e0eCAFs\u76f8\u4e92\u4f5c\u7528\uff0c\u523a\u6fc0\u7ec6\u80de\u5916\u57fa\u8d28\u91cd\u5851\uff0c\u4fc3\u8fdbTIB\u7ed3\u6784\u5f62\u6210\uff0c\u4ece\u800c\u9650\u5236\u80bf\u7624\u6838\u5fc3\u533a\u7684\u514d\u75ab\u6d78\u6da6\u3002\u4e34\u5e8a\u524d\u5c0f\u9f20\u6a21\u578b\u4e2d\uff0c\u963b\u65adSPP1\u6216\u5de8\u566c\u7ec6\u80de\u7279\u5f02\u6027\u6572\u9664SPP1\u4f7f\u5f97\u6297PD -1\u6cbb\u7597\u5c0f\u9f20\u809d\u764c\u7684\u7597\u6548\u589e\u5f3a\uff0c\u540c\u65f6\u4f34\u6709CAF\u6d78\u6da6\u51cf\u5c11\u548c\u7ec6\u80de\u6bd2\u6027T\u7ec6\u80de\u6d78\u6da6\u589e\u52a0\u3002<\/p>\n

Conclusions: <\/strong>We identified that the TIB structure formed by the interaction of SPP1+ macrophages and CAFs is related to immunotherapy efficacy. Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC.<\/p>\n

\u6211\u4eec\u53d1\u73b0SPP1+\u5de8\u566c\u7ec6\u80de\u4e0eCAFs\u76f8\u4e92\u4f5c\u7528\u5f62\u6210\u7684TIB\u7ed3\u6784\u4e0e\u514d\u75ab\u6cbb\u7597\u6548\u679c\u76f8\u5173\u3002\u56e0\u6b64\uff0c\u901a\u8fc7\u963b\u65adSPP1\u7834\u574fTIB\u7ed3\u6784\u53ef\u80fd\u6210\u4e3a\u589e\u5f3a\u809d\u764c\u514d\u75ab\u68c0\u67e5\u70b9\u963b\u65ad\u6cbb\u7597\u6548\u679c\u7684\u6cbb\u7597\u65b9\u6cd5\u3002<\/p>\n

Impact and implications: Only a limited number of patients with hepatocellular carcinoma (HCC) benefit from tumour immunotherapy, which significantly hinders its application. Herein, we used multiomics to identify the spatial structure of the tumour immune barrier (TIB), which is formed by the interaction of SPP1+ macrophages and cancer-associated fibroblasts in the HCC microenvironment. This structure constrains immunotherapy efficacy by limiting immune cell infiltration into malignant regions. Preclinically, we revealed that blocking SPP1 or macrophage-specific deletion of Spp1 in mice could destroy the TIB structure and sensitize HCC cells to immunotherapy. These results provide the first key steps towards finding more effective therapies for HCC and have implications for physicians, scientists, and drug developers in the field of HCC.<\/p>\n

\u53ea\u6709\u6709\u9650\u7684\u809d\u7ec6\u80de\u764c(HCC)\u60a3\u8005\u80fd\u4ece\u80bf\u7624\u514d\u75ab\u6cbb\u7597\u4e2d\u83b7\u76ca\uff0c\u8fd9\u663e\u8457\u963b\u788d\u4e86\u5176\u5e94\u7528\u3002\u5728\u672c\u7814\u7a76\u4e2d\uff0c\u6211\u4eec\u4f7f\u7528\u591a\u7ec4\u5b66\u6765\u786e\u5b9a\u80bf\u7624\u514d\u75ab\u5c4f\u969c(TIB)\u7684\u7a7a\u95f4\u7ed3\u6784\uff0c\u8be5\u5c4f\u969c\u662f\u7531SPP1+\u5de8\u566c\u7ec6\u80de\u548c\u80bf\u7624\u76f8\u5173\u6210\u7ea4\u7ef4\u7ec6\u80de\u5728HCC\u5fae\u73af\u5883\u4e2d\u76f8\u4e92\u4f5c\u7528\u5f62\u6210\u7684\u3002\u8fd9\u79cd\u7ed3\u6784\u901a\u8fc7\u9650\u5236\u514d\u75ab\u7ec6\u80de\u6d78\u6da6\u5230\u6076\u6027\u533a\u57df\u6765\u9650\u5236\u514d\u75ab\u6cbb\u7597\u7684\u6548\u679c\u3002\u4e34\u5e8a\u524d\uff0c\u6211\u4eec\u53d1\u73b0\u5728\u5c0f\u9f20\u4e2d\u963b\u65adSPP1\u6216\u5de8\u566c\u7ec6\u80de\u7279\u5f02\u6027\u6572\u9664SPP1\u53ef\u4ee5\u7834\u574fTIB\u7ed3\u6784\uff0c\u5e76\u4f7f\u809d\u764c\u7ec6\u80de\u5bf9\u514d\u75ab\u6cbb\u7597\u589e\u654f\u3002\u8fd9\u4e9b\u7ed3\u679c\u4e3a\u5bfb\u627e\u66f4\u6709\u6548\u7684HCC\u7597\u6cd5\u63d0\u4f9b\u4e86\u7b2c\u4e00\u4e2a\u5173\u952e\u6b65\u9aa4\uff0c\u5e76\u5bf9HCC\u9886\u57df\u7684\u533b\u5e08\u3001\u79d1\u5b66\u5bb6\u548c\u836f\u7269\u5f00\u53d1\u8005\u4ea7\u751f\u4e86\u5f71\u54cd\u3002<\/p>\n


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Keywords: <\/strong><\/p>\n

Hepatocellular carcinoma; SPP1(+) macrophage; cancer-associated fibroblast; combination therapy; single cell RNA sequencing; spatial transcriptome; tumour immune barrier.<\/p>\n

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Nat Med. 20230126<\/strong><\/p>\n<\/section>\n<\/section>\n

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Persistent mutation burden drives sustained anti-tumor immune responses<\/strong><\/p>\n

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Nat Med. 2023 Jan 26. <\/em><\/p>\n

doi: <\/strong>10.1038\/s41591-022-02163-w.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36702947\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss in a pan-cancer analysis across 31 tumor types (n = 9,242) and eight immunotherapy-treated cohorts of patients with non-small-cell lung cancer, melanoma, mesothelioma, and head and neck cancer (n = 524). We discovered that mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) which is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.<\/p>\n

\u80bf\u7624\u7a81\u53d8\u8d1f\u8377\u662f\u53cd\u6620\u80bf\u7624\u5f02\u7269\u6027\u7684\u4e00\u4e2a\u4e0d\u592a\u5b8c\u7f8e\u7684\u6307\u6807\uff0c\u56e0\u6b64\u5728\u9884\u6d4b\u514d\u75ab\u6cbb\u7597\u5e94\u7b54\u65b9\u9762\u672a\u80fd\u8f83\u597d\u5730\u8bc1\u660e\u5176\u4e34\u5e8a\u6548\u7528\u3002\u6211\u4eec\u572831\u79cd\u80bf\u7624\u7c7b\u578b(n = 9,242)\u548c8\u4e2a\u63a5\u53d7\u514d\u75ab\u6cbb\u7597\u7684\u975e\u5c0f\u7ec6\u80de\u80ba\u764c\u3001\u9ed1\u8272\u7d20\u7624\u3001\u95f4\u76ae\u7624\u548c\u5934\u9888\u764c(n = 524)\u60a3\u8005\u961f\u5217\u7684\u6cdb\u764c\u75c7\u5206\u6790\u4e2d\uff0c\u8bc4\u4f30\u4e86\u57fa\u56e0\u7ec4\u4e2d\u4e0d\u592a\u53ef\u80fd\u53d1\u751f\u7f3a\u5931\u7684\u533a\u57df\u7684\u7a81\u53d8\u3002\u6211\u4eec\u53d1\u73b0\uff0c\u5355\u62f7\u8d1d\u533a\u57df\u7684\u7a81\u53d8\u548c\u6bcf\u4e2a\u7ec6\u80de\u4e2d\u5b58\u5728\u591a\u62f7\u8d1d\u7684\u7a81\u53d8\u6784\u6210\u6301\u7eed\u6027\u80bf\u7624\u7a81\u53d8\u8d1f\u8377(pTMB)\uff0c pTMB\u4e0e\u5bf9\u514d\u75ab\u68c0\u67e5\u70b9\u963b\u65ad\u7684\u6cbb\u7597\u5e94\u7b54\u76f8\u5173\u3002\u5728\u514d\u75ab\u6cbb\u7597\u7684\u9009\u62e9\u538b\u529b\u4e0b\uff0c\u6301\u7eed\u6027\u7a81\u53d8\u5728\u80bf\u7624\u8fdb\u5316\u7684\u80cc\u666f\u4e0b\u4fdd\u6301\uff0c\u800cpTMB\u542b\u91cf\u9ad8\u7684\u80bf\u7624\u5177\u6709\u66f4\u708e\u75c7\u7684\u80bf\u7624\u5fae\u73af\u5883\u7279\u5f81\u3002pTMB\u5e26\u6765\u4e86\u764c\u7ec6\u80de\u65e0\u6cd5\u514b\u670d\u7684\u8fdb\u5316\u74f6\u9888\uff0c\u56e0\u6b64\u53ef\u80fd\u9a71\u52a8\u514d\u75ab\u6cbb\u7597\u80cc\u666f\u4e0b\u7684\u6301\u7eed\u6297\u80bf\u7624\u514d\u75ab\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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Pharmacol Ther. 20230123<\/strong><\/p>\n<\/section>\n<\/section>\n

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Extracellular vesicle-based therapeutics: Extracellular vesicles as therapeutic targets and agents<\/strong><\/p>\n

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Pharmacol Ther. 2023 Jan 23;108352. <\/em><\/p>\n

doi: <\/strong>10.1016\/j.pharmthera.2023.108352.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36702209\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Extracellular vesicles (EVs) are cell-derived membrane vesicles composed of a lipid bilayer. EVs contain biological molecules, such as nucleic acids, lipids, and proteins. As these molecules are transferred to cells that receive EVs, EVs function as intercellular communication tools. EV-mediated intercellular communication is involved in various diseases, such as cancer and neurodegenerative diseases, and biological events, such as immune reactions and inflammation. Therefore, EVs are suggested to be useful as therapeutic targets for various diseases. However, an EV-based drug delivery system (DDS) that utilizes its therapeutic properties has not yet been reported. The biological activities of EVs are derived from their endogenous components; hence, they can be directly applied as drugs. In this review, the basic aspects of EVs, such as their types, methods of isolation, and in vivo behavior, are briefly summarized. Moreover, the potential of using therapeutics targeting EVs has been discussed in cancer and neurodegenerative diseases. Various therapeutics using EVs, including DDSs, are listed and their associated advantages and challenges are discussed.<\/p>\n

\u5916\u6ccc\u4f53(Extracellular vesicles, EVs)\u662f\u7531\u8102\u8d28\u53cc\u5206\u5b50\u5c42\u7ec4\u6210\u7684\u7ec6\u80de\u6e90\u6027\u819c\u6027\u56ca\u6ce1\u3002EVs\u542b\u6709\u6838\u9178\u3001\u8102\u8d28\u548c\u86cb\u767d\u8d28\u7b49\u751f\u7269\u5206\u5b50\u3002\u5f53\u8fd9\u4e9b\u5206\u5b50\u88ab\u8f6c\u79fb\u5230\u63a5\u53d7EVs\u7684\u7ec6\u80de\u65f6\uff0cEVs\u5c31\u6210\u4e3a\u7ec6\u80de\u95f4\u901a\u8baf\u7684\u5de5\u5177\u3002EV\u4ecb\u5bfc\u7684\u7ec6\u80de\u95f4\u901a\u8baf\u53c2\u4e0e\u591a\u79cd\u75be\u75c5\uff0c\u5982\u764c\u75c7\u3001\u795e\u7ecf\u9000\u884c\u6027\u75be\u75c5\u7b49\uff0c\u4ee5\u53ca\u514d\u75ab\u53cd\u5e94\u3001\u708e\u75c7\u7b49\u751f\u7269\u5b66\u4e8b\u4ef6\u3002\u56e0\u6b64\uff0cEVs\u88ab\u8ba4\u4e3a\u662f\u591a\u79cd\u75be\u75c5\u7684\u6709\u6548\u6cbb\u7597\u9776\u70b9\u3002\u7136\u800c\uff0c\u5229\u7528\u5176\u6cbb\u7597\u7279\u6027\u7684\u57fa\u4e8eEV\u7684\u836f\u7269\u9012\u9001\u7cfb\u7edf(DDS)\u5c1a\u672a\u89c1\u62a5\u9053\u3002EVs\u7684\u751f\u7269\u6d3b\u6027\u6765\u6e90\u4e8e\u5176\u5185\u6e90\u6027\u6210\u5206\uff1b\u56e0\u6b64\uff0c\u5b83\u4eec\u53ef\u4ee5\u76f4\u63a5\u4f5c\u4e3a\u836f\u7269\u5e94\u7528\u3002\u672c\u6587\u5c31EVs\u7684\u7c7b\u578b\u3001\u5206\u79bb\u65b9\u6cd5\u53ca\u5728\u4f53\u884c\u4e3a\u7b49\u65b9\u9762\u7684\u7814\u7a76\u8fdb\u5c55\u4f5c\u4e00\u7efc\u8ff0\u3002\u6b64\u5916\uff0c\u9488\u5bf9EVs\u7684\u6cbb\u7597\u836f\u7269\u5728\u764c\u75c7\u548c\u795e\u7ecf\u9000\u884c\u6027\u75be\u75c5\u4e2d\u7684\u5e94\u7528\u4e5f\u5f97\u5230\u4e86\u8ba8\u8bba\u3002\u672c\u6587\u5217\u51fa\u4e86\u4f7f\u7528EVs(\u5305\u62ecDDSs)\u7684\u5404\u79cd\u6cbb\u7597\u65b9\u6cd5\uff0c\u5e76\u8ba8\u8bba\u4e86\u5176\u76f8\u5173\u7684\u4f18\u52bf\u548c\u6311\u6218\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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04<\/strong><\/p>\n<\/section>\n<\/section>\n

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Nat Rev Drug Discov. 20230124<\/strong><\/p>\n<\/section>\n<\/section>\n

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Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders<\/strong><\/p>\n

\u80bf\u7624\u514d\u75ab\u6cbb\u7597\u548c\u81ea\u8eab\u514d\u75ab\u6027\u75be\u75c5\u4e2d\u9776\u5411\u86cb\u767d\u78f7\u9178\u9176<\/strong><\/span><\/p>\n


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Nat Rev Drug Discov. 2023 Jan 24;1-22. <\/em><\/p>\n

doi: <\/strong>10.1038\/s41573-022-00618-w.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36693907\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Protein phosphatases act as key regulators of multiple important cellular processes and are attractive therapeutic targets for various diseases. Although extensive effort has been dedicated to phosphatase-targeted drug discovery, early expeditions for competitive phosphatase inhibitors were plagued by druggability issues, leading to the stigmatization of phosphatases as difficult targets. Despite challenges, persistent efforts have led to the identification of several drug-like, non-competitive modulators of some of these enzymes – including SH2 domain-containing protein tyrosine phosphatase 2, protein tyrosine phosphatase 1B, vascular endothelial protein tyrosine phosphatase and protein phosphatase 1 – reigniting interest in therapeutic targeting of phosphatases. Here, we discuss recent progress in phosphatase drug discovery, with emphasis on the development of selective modulators that exhibit biological activity. The roles and regulation of protein phosphatases in immune cells and their potential as powerful targets for immuno-oncology and autoimmunity indications are assessed.<\/p>\n

\u86cb\u767d\u78f7\u9178\u9176\u662f\u591a\u79cd\u91cd\u8981\u7ec6\u80de\u8fc7\u7a0b\u7684\u5173\u952e\u8c03\u8282\u56e0\u5b50\uff0c\u4e5f\u662f\u5404\u79cd\u75be\u75c5\u4e2d\u6709\u5438\u5f15\u529b\u7684\u6cbb\u7597\u9776\u70b9\u3002\u5c3d\u7ba1\u5728\u78f7\u9178\u9176\u9776\u5411\u836f\u7269\u7684\u53d1\u73b0\u65b9\u9762\u5df2\u7ecf\u4ed8\u51fa\u4e86\u5927\u91cf\u7684\u52aa\u529b\uff0c\u4f46\u65e9\u671f\u7ade\u4e89\u6027\u78f7\u9178\u9176\u6291\u5236\u5242\u7684\u5f00\u53d1\u53d7\u5230\u836f\u7269\u654f\u611f\u6027\u95ee\u9898\u7684\u56f0\u6270\uff0c\u5bfc\u81f4\u78f7\u9178\u9176\u88ab\u79f0\u4e3a\u56f0\u96be\u7684\u9776\u70b9\u3002\u5c3d\u7ba1\u5b58\u5728\u6311\u6218\uff0c\u4f46\u901a\u8fc7\u4e0d\u61c8\u52aa\u529b\uff0c\u6211\u4eec\u53d1\u73b0\u4e86\u5176\u4e2d\u4e00\u4e9b\u9176\u7684\u51e0\u79cd\u7c7b\u836f\u7269\u3001\u975e\u7ade\u4e89\u6027\u8c03\u8282\u5242(\u5305\u62ec\u5305\u542bSH2\u7ed3\u6784\u57df\u7684\u86cb\u767d\u916a\u6c28\u9178\u78f7\u9178\u91762\u3001\u86cb\u767d\u916a\u6c28\u9178\u78f7\u9178\u91761B\u3001\u8840\u7ba1\u5185\u76ae\u86cb\u767d\u916a\u6c28\u9178\u78f7\u9178\u9176\u548c\u86cb\u767d\u78f7\u9178\u91761)\uff0c\u8fd9\u91cd\u65b0\u70b9\u71c3\u4e86\u4eba\u4eec\u5bf9\u78f7\u9178\u9176\u9776\u5411\u6cbb\u7597\u7684\u5174\u8da3\u3002\u672c\u6587\u7efc\u8ff0\u4e86\u78f7\u9178\u9176\u7c7b\u836f\u7269\u7684\u7814\u7a76\u8fdb\u5c55\uff0c\u91cd\u70b9\u4ecb\u7ecd\u4e86\u5177\u6709\u751f\u7269\u6d3b\u6027\u7684\u9009\u62e9\u6027\u78f7\u9178\u9176\u8c03\u8282\u5242\u7684\u5f00\u53d1\u3002\u8bc4\u4f30\u514d\u75ab\u7ec6\u80de\u4e2d\u86cb\u767d\u78f7\u9178\u9176\u7684\u4f5c\u7528\u548c\u8c03\u8282\uff0c\u4ee5\u53ca\u5b83\u4eec\u4f5c\u4e3a\u514d\u75ab\u80bf\u7624\u548c\u81ea\u8eab\u514d\u75ab\u9002\u5e94\u8bc1\u7684\u5f3a\u5927\u9776\u70b9\u7684\u6f5c\u529b\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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05<\/strong><\/p>\n<\/section>\n<\/section>\n

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Cell. 20230119<\/strong><\/p>\n<\/section>\n<\/section>\n

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Multiplexed 3D atlas of state transitions and immune interaction in colorectal cancer<\/strong><\/p>\n

\u7ed3\u76f4\u80a0\u764c\u72b6\u6001\u8f6c\u6362\u548c\u514d\u75ab\u76f8\u4e92\u4f5c\u7528\u7684\u591a\u91cd3D\u56fe\u8c31<\/strong><\/span><\/p>\n


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Cell. 2023 Jan 19;186(2):363-381.e19. <\/em><\/p>\n

doi: <\/strong>10.1016\/j.cell.2022.12.028.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36669472\/<\/span><\/p>\n


<\/p>\n

Abstract<\/strong><\/span><\/p>\n

Advanced solid cancers are complex assemblies of tumor, immune, and stromal cells characterized by high intratumoral variation. We use highly multiplexed tissue imaging, 3D reconstruction, spatial statistics, and machine learning to identify cell types and states underlying morphological features of known diagnostic and prognostic significance in colorectal cancer. Quantitation of these features in high-plex marker space reveals recurrent transitions from one tumor morphology to the next, some of which are coincident with long-range gradients in the expression of oncogenes and epigenetic regulators. At the tumor invasive margin, where tumor, normal, and immune cells compete, T cell suppression involves multiple cell types and 3D imaging shows that seemingly localized 2D features such as tertiary lymphoid structures are commonly interconnected and have graded molecular properties. Thus, while cancer genetics emphasizes the importance of discrete changes in tumor state, whole-specimen imaging reveals large-scale morphological and molecular gradients analogous to those in developing tissues.<\/p>\n

\u665a\u671f\u5b9e\u4f53\u764c\u662f\u80bf\u7624\u3001\u514d\u75ab\u548c\u95f4\u8d28\u7ec6\u80de\u7684\u590d\u6742\u7ec4\u5408\uff0c\u5176\u7279\u5f81\u662f\u7624\u5185\u9ad8\u5ea6\u53d8\u5f02\u3002\u6211\u4eec\u4f7f\u7528\u9ad8\u5ea6\u591a\u91cd\u7684\u7ec4\u7ec7\u6210\u50cf\u30013D\u91cd\u5efa\u3001\u7a7a\u95f4\u7edf\u8ba1\u548c\u673a\u5668\u5b66\u4e60\u6765\u8bc6\u522b\u7ed3\u76f4\u80a0\u764c\u4e2d\u5177\u6709\u5df2\u77e5\u8bca\u65ad\u548c\u9884\u540e\u610f\u4e49\u7684\u5f62\u6001\u7279\u5f81\u57fa\u7840\u4e0a\u7684\u7ec6\u80de\u7c7b\u578b\u548c\u72b6\u6001\u3002\u5728\u9ad8\u901a\u91cf\u6807\u8bb0\u7a7a\u95f4\u5bf9\u8fd9\u4e9b\u7279\u5f81\u8fdb\u884c\u5b9a\u91cf\u5206\u6790\uff0c\u63ed\u793a\u4e86\u4ece\u4e00\u79cd\u80bf\u7624\u5f62\u6001\u5230\u4e0b\u4e00\u79cd\u80bf\u7624\u5f62\u6001\u7684\u53cd\u590d\u8f6c\u53d8\uff0c\u5176\u4e2d\u4e00\u4e9b\u4e0e\u764c\u57fa\u56e0\u548c\u8868\u89c2\u9057\u4f20\u8c03\u8282\u56e0\u5b50\u8868\u8fbe\u7684\u957f\u671f\u68af\u5ea6\u4e00\u81f4\u3002\u5728\u80bf\u7624\u6d78\u6da6\u8fb9\u7f18\uff0c\u80bf\u7624\u7ec6\u80de\u3001\u6b63\u5e38\u7ec6\u80de\u548c\u514d\u75ab\u7ec6\u80de\u76f8\u4e92\u7ade\u4e89\uff0cT\u7ec6\u80de\u6291\u5236\u6d89\u53ca\u591a\u79cd\u7ec6\u80de\u7c7b\u578b\uff0c3D\u6210\u50cf\u663e\u793a\u770b\u4f3c\u5c40\u9650\u76842D\u7279\u5f81(\u5982\u4e09\u7ea7\u6dcb\u5df4\u7ed3\u6784)\u901a\u5e38\u76f8\u4e92\u8fde\u63a5\uff0c\u5e76\u5177\u6709\u5206\u7ea7\u7684\u5206\u5b50\u7279\u6027\u3002\u56e0\u6b64\uff0c\u867d\u7136\u764c\u75c7\u9057\u4f20\u5b66\u5f3a\u8c03\u4e86\u80bf\u7624\u72b6\u6001\u79bb\u6563\u53d8\u5316\u7684\u91cd\u8981\u6027\uff0c\u4f46\u5168\u6837\u672c\u6210\u50cf\u63ed\u793a\u4e86\u4e0e\u53d1\u80b2\u7ec4\u7ec7\u7c7b\u4f3c\u7684\u5927\u89c4\u6a21\u5f62\u6001\u548c\u5206\u5b50\u68af\u5ea6\u3002<\/p>\n


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Keywords: <\/strong><\/p>\n

3D microscopy; PD1-PDL1 interaction; cellular; colorectal cancer; intermixed molecular; large-scale; morphological features; multiplexed imaging; spatial gradients; spatial proteomics; spatial transcriptomics; tertiary lymphoid structures; tumor atlas; tumor budding.<\/p>\n

\u4e09\u7ef4\u663e\u5fae\u955c\uff1bPD1-PDL1\u4e92\u4f5c\uff1b\u7ec6\u80de\uff1b\u7ed3\u76f4\u80a0\u764c\uff1b\u6df7\u6742\u5728\u4e00\u8d77\u7684\u5206\u5b50\uff1b\u5927\u89c4\u6a21\u7684\uff1b\u5f62\u6001\u5b66\u7279\u5f81\uff1b\u591a\u91cd\u6210\u50cf\uff1b\u7a7a\u95f4\u68af\u5ea6\uff1b\u7a7a\u95f4\u86cb\u767d\u8d28\u7ec4\u5b66\uff1b\u7a7a\u95f4\u8f6c\u5f55\u7ec4\uff1b\u4e09\u7ea7\u6dcb\u5df4\u7ed3\u6784\uff1b\u80bf\u7624\u56fe\u8c31\uff1b\u80bf\u7624\u840c\u82bd\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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06<\/strong><\/p>\n<\/section>\n<\/section>\n

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Nat Med. 20230119<\/strong><\/p>\n<\/section>\n<\/section>\n

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Bodywide ecological interventions on cancer<\/strong><\/p>\n

\u764c\u75c7\u7684\u5168\u8eab\u751f\u6001\u5e72\u9884<\/strong><\/span><\/p>\n


<\/strong><\/span><\/p>\n

Nat Med. 2023 Jan 19. <\/em><\/p>\n

doi: <\/strong>Nat Med. 2023 Jan 19. <\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36658422\/<\/span><\/p>\n


<\/p>\n

Abstract<\/strong><\/span><\/p>\n

Historically, cancer research and therapy have focused on malignant cells and their tumor microenvironment. However, the vascular, lymphatic and nervous systems establish long-range communication between the tumor and the host. This communication is mediated by metabolites generated by the host or the gut microbiota, as well by systemic neuroendocrine, pro-inflammatory and immune circuitries-all of which dictate the trajectory of malignant disease through molecularly defined biological mechanisms. Moreover, aging, co-morbidities and co-medications have a major impact on the development, progression and therapeutic response of patients with cancer. In this Perspective, we advocate for a whole-body ‘ecological’ exploration of malignant disease. We surmise that accumulating knowledge on the intricate relationship between the host and the tumor will shape rational strategies for systemic, bodywide interventions that will eventually improve tumor control, as well as quality of life, in patients with cancer.<\/p>\n

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Neuro Oncol. 20230119<\/strong><\/p>\n<\/section>\n<\/section>\n

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Single-cell transcriptomic analyses provide insights into the cellular origins and drivers of brain metastasis from lung adenocarcinoma<\/strong><\/p>\n

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Neuro Oncol. 2023 Jan 19;noad017. <\/em><\/p>\n

doi: <\/strong>10.1093\/neuonc\/noad017.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36656750\/<\/span><\/p>\n


<\/p>\n

Abstract<\/strong><\/span><\/p>\n

Background:<\/strong> Brain metastasis (BM) is the most common intracranial malignancy causing significant mortality, and lung cancer is the most common origin of BM. However, the cellular origins and drivers of BM from lung adenocarcinoma (LUAD) have yet to be defined.<\/p>\n

\u8111\u8f6c\u79fb(BM)\u662f\u6700\u5e38\u89c1\u7684\u9885\u5185\u6076\u6027\u80bf\u7624\uff0c\u6b7b\u4ea1\u7387\u9ad8\uff0c\u80ba\u764c\u662f\u6700\u5e38\u89c1\u7684BM\u6765\u6e90\u3002\u7136\u800c\uff0c\u80ba\u817a\u764c\u9aa8\u9ad3\u7684\u7ec6\u80de\u8d77\u6e90\u548c\u9a71\u52a8\u56e0\u7d20\u5c1a\u672a\u660e\u786e\u3002<\/p>\n

Methods:<\/strong> The cellular constitutions were characterized by single-cell transcriptomic profiles of 11 LUAD primary tumor (PT) and 10 BM samples (GSE131907). Copy number variation (CNV) and clonality analysis were applied to illustrate cellular origins of BM tumors. Brain metastasis-associated epithelial cells (BMAECs) were identified by pseudotime trajectory analysis. By using machine-learning algorithms, we developed the BM-index representing the relative abundance of BMAECs in the bulk RNA-seq data, indicating high risk of BM. Therapeutic drugs targeting BMAECs were predicted based on the drug sensitivity data of cancer cell lines.<\/p>\n

\u901a\u8fc711\u4f8b\u80ba\u817a\u764c\u539f\u53d1\u80bf\u7624(PT)\u548c10\u4f8b\u80ba\u817a\u764c\u9aa8\u9ad3(GSE131907)\u7684\u5355\u7ec6\u80de\u8f6c\u5f55\u7ec4\u8c31\uff0c\u5206\u6790\u5176\u7ec6\u80de\u7ec4\u6210\u3002\u5e94\u7528\u62f7\u8d1d\u6570\u53d8\u5f02(CNV)\u548c\u514b\u9686\u6027\u5206\u6790\u6765\u8bf4\u660e\u9aa8\u9ad3\u80bf\u7624\u7684\u7ec6\u80de\u8d77\u6e90\u3002\u901a\u8fc7\u9006\u65f6\u5e8f\u8f68\u8ff9\u5206\u6790\u9274\u5b9a\u8111\u8f6c\u79fb\u76f8\u5173\u4e0a\u76ae\u7ec6\u80de(BMAECs)\u3002\u901a\u8fc7\u673a\u5668\u5b66\u4e60\u7b97\u6cd5\uff0c\u6211\u4eec\u5efa\u7acb\u4e86\u4ee3\u8868\u5927\u6837\u672cRNA-seq\u6570\u636e\u4e2dBMAECs\u76f8\u5bf9\u4e30\u5ea6\u7684BM\u6307\u6570\uff08BM-index\uff09\uff0c\u8be5\u6307\u6570\u8d8a\u9ad8\u8868\u660eBM\u98ce\u9669\u8d8a\u9ad8\u3002\u6839\u636e\u80bf\u7624\u7ec6\u80de\u7cfb\u836f\u7269\u654f\u611f\u6027\u6570\u636e\u9884\u6d4b\u9776\u5411BMAECs\u7684\u6cbb\u7597\u836f\u7269\u3002<\/p>\n

Results:<\/strong> Differences in macrophages and T cells between PTs and BMs were investigated by single-cell RNA (scRNA) and immunohistochemistry and immunofluorescence data. CNV analysis demonstrated BM was derived from subclones of PT with a gain of chromosome 7. We then identified BMAECs and its biomarker, S100A9. Immunofluorescence indicated strong correlations of BMAECs with metastasis and prognosis evaluated by the paired PT and BM samples from Peking Union Medical College Hospital (PUMCH). We further evaluated the clinical significance of BM-index and identified 7 drugs that potentially target BMAECs.<\/p>\n

\u901a\u8fc7\u5355\u7ec6\u80deRNA (scRNA)\u3001\u514d\u75ab\u7ec4\u7ec7\u5316\u5b66\u548c\u514d\u75ab\u8367\u5149\u6570\u636e\u7814\u7a76PTs\u548cBMs\u4e4b\u95f4\u5de8\u566c\u7ec6\u80de\u548cT\u7ec6\u80de\u7684\u5dee\u5f02\u3002CNV\u5206\u6790\u663e\u793a\u9aa8\u9ad3\u6765\u6e90\u4e8e\u83b7\u5f977\u53f7\u67d3\u8272\u4f53\u7684PT\u4e9a\u514b\u9686\u3002\u7136\u540e\u6211\u4eec\u9274\u5b9a\u4e86BMAECs\u53ca\u5176\u751f\u7269\u6807\u5fd7\u7269S100A9\u3002\u5317\u4eac\u534f\u548c\u533b\u9662\u914d\u5bf9\u7684PT\u548cBM\u6807\u672c\u514d\u75ab\u8367\u5149\u7ed3\u679c\u663e\u793a\uff0cBMAECs\u4e0e\u8f6c\u79fb\u548c\u9884\u540e\u5bc6\u5207\u76f8\u5173\u3002\u6211\u4eec\u8fdb\u4e00\u6b65\u8bc4\u4f30\u4e86BM-index\u7684\u4e34\u5e8a\u610f\u4e49\uff0c\u5e76\u786e\u5b9a\u4e867\u79cd\u6f5c\u5728\u7684\u9776\u5411BMAECs\u7684\u836f\u7269\u3002<\/p>\n

Conclusions:<\/strong> This study clarified possible cellular origins and drivers of metastatic LUAD at single cell level, and laid a foundation for early detections of LUAD patients with a high risk of BM.<\/p>\n

\u672c\u7814\u7a76\u5728\u5355\u7ec6\u80de\u6c34\u5e73\u4e0a\u9610\u660e\u4e86\u8f6c\u79fb\u6027LUAD\u53ef\u80fd\u7684\u7ec6\u80de\u6765\u6e90\u548c\u9a71\u52a8\u56e0\u7d20\uff0c\u4e3a\u65e9\u671f\u53d1\u73b0BM\u9ad8\u98ce\u9669LUAD\u60a3\u8005\u5960\u5b9a\u4e86\u57fa\u7840\u3002<\/p>\n


<\/p>\n

Keywords: <\/strong><\/p>\n

Brain metastasis; Immune microenvironment; Lung adenocarcinoma; S100A9; scRNA-seq.<\/p>\n

\u8111\u8f6c\u79fb\uff1b\u514d\u75ab\u5fae\u73af\u5883\uff1b\u80ba\u817a\u764c\uff1bS100A9\uff1bscRNA-seq\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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08<\/strong><\/p>\n<\/section>\n<\/section>\n

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Cancer Discov. 20230117<\/strong><\/p>\n<\/section>\n<\/section>\n

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\u2726<\/p>\n<\/section>\n<\/section>\n

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Targeting Microglial Metabolic Rewiring Synergizes with Immune Checkpoint Blockade Therapy for Glioblastoma<\/strong><\/p>\n

\u5728\u80f6\u8d28\u6bcd\u7ec6\u80de\u7624\u4e2d\u9776\u5411\u5c0f\u80f6\u8d28\u7ec6\u80de\u4ee3\u8c22\u91cd\u7ec4\u5bf9\u514d\u75ab\u68c0\u67e5\u70b9\u963b\u65ad\u7597\u6cd5\u6709\u589e\u6548\u4f5c\u7528<\/strong><\/span><\/p>\n


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Cancer Discov. 2023 Jan 17;CD-22-0455. <\/em><\/p>\n

doi: <\/strong>10.1158\/2159-8290.CD-22-0455.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36649564\/<\/span><\/p>\n


<\/p>\n

Abstract<\/strong><\/span><\/p>\n

Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+\/-) or microglia-specific Nr4a2 (Nr4a2fl\/flCx3cr1cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacological NR4A2 inhibition attenuated the pro-tumorigenic TIME, and targeting the NR4A2 or SQLE enhanced therapeutic efficacy of immune checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2-SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer.<\/p>\n

\u80f6\u8d28\u6bcd\u7ec6\u80de\u7624(GBM)\u662f\u6700\u81f4\u547d\u7684\u539f\u53d1\u6027\u8111\u80bf\u7624\uff0c\u514d\u75ab\u6cbb\u7597\u5bf9\u5176\u7597\u6548\u6709\u9650\u3002GBM\u590d\u6742\u7684\u80bf\u7624\u514d\u75ab\u5fae\u73af\u5883(tumor immune microenvironment, TIME)\u53cd\u6620\u4e86\u72ec\u7279\u7684\u8111\u514d\u75ab\u666f\u89c2\u3002\u5728\u8fd9\u91cc\uff0cGBM TIME\u7684\u5355\u7ec6\u80de\u6d4b\u5e8f\u663e\u793a\uff0c\u5c0f\u80f6\u8d28\u7ec6\u80de\u5904\u4e8e\u4e25\u91cd\u7684\u6c27\u5316\u5e94\u6fc0\u4e2d\uff0c\u8fd9\u8bf1\u5bfc\u4e86\u5c0f\u80f6\u8d28\u7ec6\u80de\u4e2d\u6838\u53d7\u4f53\u4e9a\u5bb6\u65cf4A\u6210\u54582 (NR4A2)\u4f9d\u8d56\u7684\u8f6c\u5f55\u6d3b\u6027\u3002\u6742\u5408\u5b50Nr4a2 (Nr4a2+\/-)\u6216\u5c0f\u80f6\u8d28\u7ec6\u80de\u7279\u5f02\u6027Nr4a2 (Nr4a2fl\/flCx3cr1cre)\u57fa\u56e0\u9776\u5411\u6572\u9664\u901a\u8fc7\u51cf\u5c11GBM\u4e2d\u6fc0\u6d3b\u7684\u5c0f\u80f6\u8d28\u7ec6\u80de\u548c\u589e\u5f3aCD8+ T\u7ec6\u80de\u7684\u6297\u539f\u63d0\u5448\u80fd\u529b\u6765\u91cd\u5851\u4f53\u5185\u5c0f\u80f6\u8d28\u7ec6\u80de\u7684\u53ef\u5851\u6027\u3002\u5728\u5c0f\u80f6\u8d28\u7ec6\u80de\u4e2d\uff0cNR4A2\u6fc0\u6d3b\u89d2\u9ca8\u70ef\u5355\u52a0\u6c27\u9176(SQLE)\uff0c\u5bfc\u81f4\u80c6\u56fa\u9187\u7a33\u6001\u5931\u8c03\u3002\u836f\u7406\u6291\u5236NR4A2\u51cf\u5f31\u4e86\u4fc3\u80bf\u7624\u53d1\u751f\u7684TIME\uff0c\u9776\u5411NR4A2\u6216SQLE\u589e\u5f3a\u4e86\u514d\u75ab\u68c0\u67e5\u70b9\u963b\u65ad\u5728\u4f53\u5185\u7684\u6cbb\u7597\u6548\u679c\u3002\u7efc\u4e0a\u6240\u8ff0\uff0c\u6c27\u5316\u5e94\u6fc0\u901a\u8fc7NR4A2-SQLE\u5728\u5c0f\u80f6\u8d28\u7ec6\u80de\u4e2d\u7684\u6d3b\u6027\u4fc3\u8fdb\u80bf\u7624\u751f\u957f\uff0c\u4e3a\u8111\u764c\u7684\u65b0\u578b\u514d\u75ab\u6cbb\u7597\u63d0\u4f9b\u4e86\u65b0\u7684\u601d\u8def\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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09<\/strong><\/p>\n<\/section>\n<\/section>\n

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Signal Transduct Target Ther. 20230116<\/strong><\/p>\n<\/section>\n<\/section>\n

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Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy<\/strong><\/p>\n

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Signal Transduct Target Ther. 2023 Jan 16;8(1):35. <\/em><\/p>\n

doi: <\/strong>10.1038\/s41392-022-01304-4.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36646684\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Microorganisms, including bacteria, viruses, fungi, and other eukaryotes, play critical roles in human health. An altered microbiome can be associated with complex diseases. Intratumoral microbial components are found in multiple tumor tissues and are closely correlated with cancer initiation and development and therapy efficacy. The intratumoral microbiota may contribute to promotion of the initiation and progression of cancers by DNA mutations, activating carcinogenic pathways, promoting chronic inflammation, complement system, and initiating metastasis. Moreover, the intratumoral microbiota may not only enhance antitumor immunity via mechanisms including STING signaling activation, T and NK cell activation, TLS production, and intratumoral microbiota-derived antigen presenting, but also decrease antitumor immune responses and promote cancer progression through pathways including upregulation of ROS, promoting an anti-inflammatory environment, T cell inactivation, and immunosuppression. The effect of intratumoral microbiota on antitumor immunity is dependent on microbiota composition, crosstalk between microbiota and the cancer, and status of cancers. The intratumoral microbiota may regulate cancer cell physiology and the immune response by different signaling pathways, including ROS, \u03b2-catenin, TLR, ERK, NF-\u03baB, and STING, among others. These viewpoints may help identify the microbiota as diagnosis or prognosis evaluation of cancers, and as new therapeutic strategy and potential therapeutic targets for cancer therapy.<\/p>\n

\u5fae\u751f\u7269\uff0c\u5305\u62ec\u7ec6\u83cc\u3001\u75c5\u6bd2\u3001\u771f\u83cc\u548c\u5176\u4ed6\u771f\u6838\u751f\u7269\uff0c\u5728\u4eba\u7c7b\u5065\u5eb7\u4e2d\u53d1\u6325\u7740\u5173\u952e\u4f5c\u7528\u3002\u5fae\u751f\u7269\u7ec4\u7684\u6539\u53d8\u53ef\u80fd\u4e0e\u590d\u6742\u75be\u75c5\u76f8\u5173\u3002\u80bf\u7624\u5185\u5fae\u751f\u7269\u6210\u5206\u5b58\u5728\u4e8e\u591a\u79cd\u80bf\u7624\u7ec4\u7ec7\u4e2d\uff0c\u4e0e\u80bf\u7624\u7684\u53d1\u751f\u3001\u53d1\u5c55\u53ca\u6cbb\u7597\u6548\u679c\u5bc6\u5207\u76f8\u5173\u3002\u80bf\u7624\u5185\u5fae\u751f\u7269\u7fa4\u53ef\u80fd\u901a\u8fc7DNA\u7a81\u53d8\u3001\u6fc0\u6d3b\u81f4\u764c\u901a\u8def\u3001\u4fc3\u8fdb\u6162\u6027\u708e\u75c7\u3001\u8865\u4f53\u7cfb\u7edf\u548c\u542f\u52a8\u8f6c\u79fb\u7b49\u65b9\u5f0f\u4fc3\u8fdb\u764c\u75c7\u7684\u53d1\u751f\u548c\u53d1\u5c55\u3002\u6b64\u5916\uff0c\u80bf\u7624\u5185\u5fae\u751f\u7269\u7fa4\u4e0d\u4ec5\u53ef\u4ee5\u901a\u8fc7STING\u4fe1\u53f7\u6fc0\u6d3b\u3001T\u7ec6\u80de\u548cNK\u7ec6\u80de\u6d3b\u5316\u3001TLS\u4ea7\u751f\u548c\u80bf\u7624\u5185\u5fae\u751f\u7269\u7fa4\u6765\u6e90\u7684\u6297\u539f\u63d0\u5448\u7b49\u673a\u5236\u589e\u5f3a\u6297\u80bf\u7624\u514d\u75ab\uff0c\u8fd8\u53ef\u4ee5\u901a\u8fc7\u4e0a\u8c03ROS\u3001\u4fc3\u8fdb\u6297\u708e\u73af\u5883\u3001T\u7ec6\u80de\u5931\u6d3b\u548c\u514d\u75ab\u6291\u5236\u7b49\u9014\u5f84\u964d\u4f4e\u6297\u80bf\u7624\u514d\u75ab\u53cd\u5e94\u548c\u4fc3\u8fdb\u80bf\u7624\u8fdb\u5c55\u3002\u80bf\u7624\u5185\u5fae\u751f\u7269\u7fa4\u5bf9\u6297\u80bf\u7624\u514d\u75ab\u7684\u4f5c\u7528\u4f9d\u8d56\u4e8e\u5fae\u751f\u7269\u7fa4\u7684\u7ec4\u6210\u3001\u5fae\u751f\u7269\u7fa4\u4e0e\u80bf\u7624\u4e4b\u95f4\u7684\u4ea4\u4e92\u4f5c\u7528\u4ee5\u53ca\u80bf\u7624\u7684\u72b6\u6001\u3002\u80bf\u7624\u5185\u83cc\u7fa4\u53ef\u80fd\u901a\u8fc7ROS\u3001\u03b2-catenin\u3001TLR\u3001ERK\u3001NF-\u03baB\u548cSTING\u7b49\u4e0d\u540c\u7684\u4fe1\u53f7\u901a\u8def\u8c03\u8282\u80bf\u7624\u7ec6\u80de\u751f\u7406\u548c\u514d\u75ab\u53cd\u5e94\u3002\u8fd9\u4e9b\u89c2\u70b9\u53ef\u80fd\u6709\u52a9\u4e8e\u8bc6\u522b\u5fae\u751f\u7269\u7fa4\u4f5c\u4e3a\u764c\u75c7\u7684\u8bca\u65ad\u6216\u9884\u540e\u8bc4\u4f30\uff0c\u5e76\u4f5c\u4e3a\u65b0\u7684\u6cbb\u7597\u7b56\u7565\u548c\u6f5c\u5728\u7684\u6cbb\u7597\u9776\u70b9\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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Nat Rev Clin Oncol. 20230113<\/strong><\/p>\n<\/section>\n<\/section>\n

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At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC<\/strong><\/p>\n

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Nat Rev Clin Oncol. 2023 Jan 13. <\/em><\/p>\n

doi: <\/strong>10.1038\/s41571-022-00718-x.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36639452\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Non-small-cell lung cancer (NSCLC) has become a paradigm of precision medicine, with the discovery of numerous disease subtypes defined by specific oncogenic driver mutations leading to the development of a range of molecularly targeted therapies. Over the past decade, rapid progress has also been made in the development of immune-checkpoint inhibitors (ICIs), especially antagonistic antibodies targeting the PD-L1-PD-1 axis, for the treatment of NSCLC. Although many of the major oncogenic drivers of NSCLC are associated with intrinsic resistance to ICIs, patients with certain oncogene-driven subtypes of the disease that are highly responsive to specific targeted therapies might also derive benefit from immunotherapy. However, the development of effective immunotherapy approaches for oncogene-addicted NSCLC has been challenged by a lack of predictive biomarkers for patient selection and limited knowledge of how ICIs and oncogene-directed targeted therapies should be combined. Therefore, whether ICIs alone or with chemotherapy or even in combination with molecularly targeted agents would offer comparable benefit in the context of selected oncogenic driver alterations to that observed in the general unselected NSCLC population remains an open question. In this Review, we discuss the effects of oncogenic driver mutations on the efficacy of ICIs and the immune tumour microenvironment as well as the potential vulnerabilities that could be exploited to overcome the challenges of immunotherapy for oncogene-addicted NSCLC.<\/p>\n

\u975e\u5c0f\u7ec6\u80de\u80ba\u764c(Non-small-cell lung cancer, NSCLC)\u5df2\u6210\u4e3a\u7cbe\u51c6\u533b\u5b66\u7684\u5178\u8303\uff0c\u591a\u79cd\u7531\u7279\u5b9a\u81f4\u764c\u9a71\u52a8\u7a81\u53d8\u5b9a\u4e49\u7684\u75be\u75c5\u4e9a\u578b\u88ab\u53d1\u73b0\uff0c\u5bfc\u81f4\u4e00\u7cfb\u5217\u5206\u5b50\u9776\u5411\u6cbb\u7597\u7684\u5f00\u53d1\u3002\u5728\u8fc7\u53bb\u7684\u5341\u5e74\u4e2d\uff0c\u514d\u75ab\u68c0\u67e5\u70b9\u6291\u5236\u5242(ICI)\uff0c\u5c24\u5176\u662f\u9776\u5411PD-L1-PD-1\u8f74\u7684\u62ee\u6297\u6297\u4f53\u5728NSCLC\u6cbb\u7597\u65b9\u9762\u4e5f\u53d6\u5f97\u4e86\u5feb\u901f\u8fdb\u5c55\u3002\u867d\u7136NSCLC\u7684\u8bb8\u591a\u4e3b\u8981\u81f4\u764c\u9a71\u52a8\u56e0\u7d20\u4e0eICI\u7684\u56fa\u6709\u8010\u836f\u76f8\u5173\uff0c\u4f46\u67d0\u4e9b\u764c\u57fa\u56e0\u9a71\u52a8\u7684\u75be\u75c5\u4e9a\u578b\u4e2d\u5bf9\u7279\u5f02\u6027\u9776\u5411\u6cbb\u7597\u6709\u9ad8\u5ea6\u5e94\u7b54\u7684\u60a3\u8005\u4e5f\u53ef\u80fd\u4ece\u514d\u75ab\u6cbb\u7597\u4e2d\u83b7\u76ca\u3002\u7136\u800c\uff0c\u7531\u4e8e\u7f3a\u4e4f\u53ef\u7528\u4e8e\u60a3\u8005\u9009\u62e9\u7684\u9884\u6d4b\u6027\u751f\u7269\u6807\u5fd7\u7269\uff0c\u4ee5\u53ca\u5bf9\u4e8eICI\u548c\u764c\u57fa\u56e0\u5bfc\u5411\u7684\u9776\u5411\u6cbb\u7597\u5982\u4f55\u7ed3\u5408\u7684\u77e5\u8bc6\u6709\u9650\uff0c\u5bf9\u764c\u57fa\u56e0\u4f9d\u8d56\u6027NSCLC\u6709\u6548\u514d\u75ab\u6cbb\u7597\u65b9\u6cd5\u7684\u5f00\u53d1\u9762\u4e34\u6311\u6218\u3002\u56e0\u6b64\uff0c\u5728\u7ecf\u8fc7\u9009\u62e9\u7684\u81f4\u764c\u9a71\u52a8\u6539\u53d8\u7684\u80cc\u666f\u4e0b\uff0cICI\u5355\u836f\u6216\u4e0e\u5316\u7597\u8054\u7528\uff0c\u751a\u81f3\u4e0e\u4e0e\u5206\u5b50\u9776\u5411\u836f\u7269\u8054\u7528\u7684\u83b7\u76ca\u662f\u5426\u4e0e\u5728\u4e00\u822c\u975e\u7ecf\u8fc7\u9009\u62e9\u7684NSCLC\u4eba\u7fa4\u4e2d\u89c2\u5bdf\u5230\u7684\u83b7\u76ca\u76f8\u5f53\u4ecd\u7136\u662f\u4e00\u4e2a\u60ac\u800c\u672a\u51b3\u7684\u95ee\u9898\u3002\u5728\u8fd9\u7bc7\u7efc\u8ff0\u4e2d\uff0c\u6211\u4eec\u8ba8\u8bba\u4e86\u81f4\u764c\u9a71\u52a8\u7a81\u53d8\u5bf9ICIs\u7597\u6548\u548c\u80bf\u7624\u514d\u75ab\u5fae\u73af\u5883\u7684\u5f71\u54cd\u4ee5\u53ca\u53ef\u4ee5\u5229\u7528\u7684\u6f5c\u5728\u5f31\u70b9\uff0c\u6765\u514b\u670d\u764c\u57fa\u56e0\u4f9d\u8d56\u7684NSCLC\u514d\u75ab\u6cbb\u7597\u4e2d\u9047\u5230\u7684\u6311\u6218\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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11<\/strong><\/p>\n<\/section>\n<\/section>\n

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Sci Adv. 20230113<\/strong><\/p>\n<\/section>\n<\/section>\n

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Escape from NK cell tumor surveillance by NGFR-induced lipid remodeling in melanoma<\/strong><\/p>\n

\u5728\u9ed1\u8272\u7d20\u7624\u4e2dNGFR\u8bf1\u5bfc\u7684\u8102\u8d28\u91cd\u5851\u4f7f\u5f97\u80bf\u7624\u7ec6\u80de\u9003\u8131NK\u7ec6\u80de\u514d\u75ab\u76d1\u89c6<\/strong><\/span><\/p>\n


<\/strong><\/span><\/p>\n

Sci Adv. 2023 Jan 13;9(2):eadc8825. Epub 2023 Jan <\/em><\/p>\n

doi: <\/strong>10.1126\/sciadv.adc8825. <\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36638181\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Metastatic disease is a major cause of death for patients with melanoma. Melanoma cells can become metastatic not only due to cell-intrinsic plasticity but also due to cancer-induced protumorigenic remodeling of the immune microenvironment. Here, we report that innate immune surveillance by natural killer (NK) cells is bypassed by human melanoma cells expressing the stem cell marker NGFR. Using in vitro and in vivo cytotoxic assays, we show that NGFR protects melanoma cells from NK cell-mediated killing and, furthermore, boosts metastasis formation in a mouse model with adoptively transferred human NK cells. Mechanistically, NGFR leads to down-regulation of NK cell activating ligands and simultaneous up-regulation of the fatty acid stearoyl-coenzyme A desaturase (SCD) in melanoma cells. Notably, pharmacological and small interfering RNA-mediated inhibition of SCD reverted NGFR-induced NK cell evasion in vitro and in vivo. Hence, NGFR orchestrates immune control antagonizing pathways to protect melanoma cells from NK cell clearance, which ultimately favors metastatic disease.<\/p>\n

\u8f6c\u79fb\u6027\u75be\u75c5\u662f\u9ed1\u8272\u7d20\u7624\u60a3\u8005\u6b7b\u4ea1\u7684\u4e3b\u8981\u539f\u56e0\u3002\u9ed1\u8272\u7d20\u7624\u7ec6\u80de\u53ef\u4ee5\u8f6c\u79fb\u4e0d\u4ec5\u7531\u4e8e\u7ec6\u80de\u5185\u5728\u7684\u53ef\u5851\u6027\uff0c\u800c\u4e14\u7531\u4e8e\u764c\u75c7\u8bf1\u5bfc\u7684\u4fc3\u764c\u6027\u514d\u75ab\u5fae\u73af\u5883\u7684\u5f62\u6210\u3002\u5728\u8fd9\u91cc\uff0c\u6211\u4eec\u62a5\u9053\u4e86\u81ea\u7136\u6740\u4f24(NK)\u7ec6\u80de\u7684\u56fa\u6709\u514d\u75ab\u76d1\u89c6\u88ab\u8868\u8fbe\u5e72\u7ec6\u80de\u6807\u8bb0\u7269NGFR\u7684\u4eba\u9ed1\u8272\u7d20\u7624\u7ec6\u80de\u6240\u907f\u5f00\u3002\u901a\u8fc7\u4f53\u5916\u548c\u4f53\u5185\u7ec6\u80de\u6bd2\u6027\u5b9e\u9a8c\uff0c\u6211\u4eec\u53d1\u73b0NGFR\u4fdd\u62a4\u9ed1\u8272\u7d20\u7624\u7ec6\u80de\u514d\u53d7NK\u7ec6\u80de\u4ecb\u5bfc\u7684\u6740\u4f24\u4f5c\u7528\uff0c\u5e76\u4e14\u5728\u8fc7\u7ee7\u8f6c\u79fb\u7684\u4ebaNK\u7ec6\u80de\u7684\u5c0f\u9f20\u6a21\u578b\u4e2d\u4fc3\u8fdb\u8f6c\u79fb\u5f62\u6210\u3002\u5728\u673a\u5236\u4e0a\uff0cNGFR\u5bfc\u81f4\u9ed1\u8272\u7d20\u7624\u7ec6\u80de\u4e2dNK\u7ec6\u80de\u6d3b\u5316\u914d\u4f53\u7684\u4e0b\u8c03\u548c\u8102\u80aa\u9178\u786c\u8102\u9170\u8f85\u9176A\u53bb\u9971\u548c\u9176(SCD)\u7684\u4e0a\u8c03\u3002\u503c\u5f97\u6ce8\u610f\u7684\u662f\uff0c\u5728\u4f53\u5185\u5916\u5b9e\u9a8c\u4e2d\uff0c\u836f\u7269\u548c\u5c0f\u5e72\u6270RNA\u4ecb\u5bfc\u7684SCD\u6291\u5236\u9006\u8f6c\u4e86NGFR\u8bf1\u5bfc\u7684NK\u7ec6\u80de\u9003\u9038\u3002\u56e0\u6b64\uff0cNGFR\u5229\u7528\u514d\u75ab\u63a7\u5236\u62ee\u6297\u901a\u8def\uff0c\u4fdd\u62a4\u9ed1\u8272\u7d20\u7624\u7ec6\u80de\u514d\u53d7NK\u7ec6\u80de\u6e05\u9664\uff0c\u6700\u7ec8\u4fc3\u4f7f\u4e86\u8f6c\u79fb\u6027\u75be\u75c5\u7684\u53d1\u751f\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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12<\/strong><\/p>\n<\/section>\n<\/section>\n

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Nature. 20230112<\/strong><\/p>\n<\/section>\n<\/section>\n

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Targeting TBK1 to overcome resistance to cancer immunotherapy<\/strong><\/p>\n

\u9776\u5411TBK1\u53ef\u514b\u670d\u764c\u75c7\u514d\u75ab\u6cbb\u7597\u7684\u8010\u836f\u6027<\/strong><\/span><\/p>\n


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Nature. 2023 Jan 12. <\/em><\/p>\n

doi: <\/strong>10.1038\/s41586-023-05704-6.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36634707\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFN\u03b3). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFN\u03b3 in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.<\/p>\n

\u5c3d\u7ba1PD-1\u963b\u65ad\u5728\u9ed1\u8272\u7d20\u7624\u548c\u5176\u4ed6\u764c\u75c7\u4e2d\u53d6\u5f97\u4e86\u6210\u529f\uff0c\u4f46\u76ee\u524d\u4ecd\u7f3a\u4e4f\u514b\u670d\u764c\u75c7\u514d\u75ab\u6cbb\u7597\u8010\u836f\u6027\u7684\u6709\u6548\u6cbb\u7597\u7b56\u7565\u3002\u5728\u8fd9\u91cc\uff0c\u6211\u4eec\u5728\u9057\u4f20\u7b5b\u9009\u4e2d\u786e\u5b9a\u4e86\u56fa\u6709\u514d\u75ab\u6fc0\u9176TANK\u7ed3\u5408\u6fc0\u91761 (TBK1)\u662f\u4e00\u4e2a\u5019\u9009\u514d\u75ab\u9003\u907f\u57fa\u56e0\u3002\u4f7f\u7528\u8de8\u591a\u4e2a\u5b9e\u9a8c\u6a21\u578b\u7684\u4e00\u5957\u9057\u4f20\u548c\u836f\u7406\u5b66\u5de5\u5177\uff0c\u6211\u4eec\u8bc1\u5b9e\u4e86TBK1\u4f5c\u4e3a\u514d\u75ab\u9003\u9038\u57fa\u56e0\u7684\u4f5c\u7528\u3002\u901a\u8fc7\u964d\u4f4e\u5bf9\u6548\u5e94\u7ec6\u80de\u56e0\u5b50(TNF\u548cIFN\u03b3)\u7684\u7ec6\u80de\u6bd2\u6027\u9608\u503c\uff0c\u9776\u5411TBK1\u589e\u5f3a\u4e86\u5bf9PD-1\u963b\u65ad\u7684\u5e94\u7b54\u3002TBK1\u6291\u5236\u8054\u5408PD-1\u963b\u65ad\u4e5f\u5728\u60a3\u8005\u6765\u6e90\u7684\u80bf\u7624\u6a21\u578b\u4e2d\u8bc1\u660e\u4e86\u7597\u6548\uff0c\u5339\u914d\u7684\u60a3\u8005\u6765\u6e90\u7684\u5668\u5b98\u578b\u80bf\u7624\u7403\u4f53\u548c\u7c7b\u5668\u5b98\u5f97\u5230\u4e86\u4e00\u81f4\u7684\u53d1\u73b0\u3002\u7f3a\u4e4fTBK1\u7684\u80bf\u7624\u7ec6\u80de\u4ee5JAK-STAT\u4f9d\u8d56\u7684\u65b9\u5f0f\u5bf9TNF\u548cIFN\u03b3\u5e94\u7b54\u800c\u7ecf\u5386RIPK\u548ccaspase\u4f9d\u8d56\u7684\u7ec6\u80de\u6b7b\u4ea1\u3002\u7efc\u4e0a\u6240\u8ff0\uff0c\u6211\u4eec\u7684\u7814\u7a76\u7ed3\u679c\u8868\u660e\uff0c\u9776\u5411TBK1\u662f\u514b\u670d\u80bf\u7624\u514d\u75ab\u6cbb\u7597\u8010\u836f\u7684\u6709\u6548\u7b56\u7565\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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13<\/strong><\/p>\n<\/section>\n<\/section>\n

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Nature. 20230111<\/strong><\/p>\n<\/section>\n<\/section>\n

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\u03b3\u03b4 T cells are effectors of immunotherapy in cancers with HLA class I defects<\/strong><\/p>\n

\u03b3\u03b4 T\u7ec6\u80de\u662fHLA-I\u7f3a\u9677\u578b\u764c\u75c7\u514d\u75ab\u6cbb\u7597\u7684\u6548\u5e94\u7ec6\u80de<\/strong><\/span><\/p>\n


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Nature. 2023 Jan 11. <\/em><\/p>\n

doi: <\/strong>10.1038\/s41586-022-05593-1.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36631610\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

DNA mismatch repair-deficient (MMR-d) cancers present an abundance of neoantigens that is thought to explain their exceptional responsiveness to immune checkpoint blockade (ICB). Here, in contrast to other cancer types, we observed that 20 out of 21 (95%) MMR-d cancers with genomic inactivation of \u03b22-microglobulin (encoded by B2M) retained responsiveness to ICB, suggesting the involvement of immune effector cells other than CD8+ T cells in this context. We next identified a strong association between B2M inactivation and increased infiltration by \u03b3\u03b4 T cells in MMR-d cancers. These \u03b3\u03b4 T cells mainly comprised the V\u03b41 and V\u03b43 subsets, and expressed high levels of PD-1, other activation markers, including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors. In vitro, PD-1+ \u03b3\u03b4 T cells that were isolated from MMR-d colon cancers exhibited enhanced reactivity to human leukocyte antigen (HLA)-class-I-negative MMR-d colon cancer cell lines and B2M-knockout patient-derived tumour organoids compared with antigen-presentation-proficient cells. By comparing paired tumour samples from patients with MMR-d colon cancer that were obtained before and after dual PD-1 and CTLA-4 blockade, we found that immune checkpoint blockade substantially increased the frequency of \u03b3\u03b4 T cells in B2M-deficient cancers. Taken together, these data indicate that \u03b3\u03b4 T cells contribute to the response to immune checkpoint blockade in patients with HLA-class-I-negative MMR-d colon cancers, and underline the potential of \u03b3\u03b4 T cells in cancer immunotherapy.<\/p>\n

DNA\u9519\u914d\u4fee\u590d\u7f3a\u9677(MMR-d)\u764c\u75c7\u5b58\u5728\u5927\u91cf\u65b0\u6297\u539f\uff0c\u8fd9\u88ab\u8ba4\u4e3a\u53ef\u4ee5\u89e3\u91ca\u5b83\u4eec\u5bf9\u514d\u75ab\u68c0\u67e5\u70b9\u963b\u65ad(ICB)\u7684\u8f83\u5f3a\u7684\u53cd\u5e94\u3002\u5728\u672c\u7814\u7a76\u4e2d\uff0c\u4e0e\u5176\u4ed6\u7c7b\u578b\u7684\u764c\u75c7\u4e0d\u540c\uff0c\u6211\u4eec\u89c2\u5bdf\u5230\u572821\u4f8b\u03b22-\u5fae\u7403\u86cb\u767d(\u7531B2M\u7f16\u7801)\u57fa\u56e0\u7ec4\u5931\u6d3b\u7684MMR-d\u764c\u75c7\u4e2d\uff0c\u670920\u4f8b(95%)\u4fdd\u7559\u4e86\u5bf9ICB\u7684\u53cd\u5e94\u6027\uff0c\u8fd9\u8868\u660e\u5728\u8fd9\u79cd\u60c5\u51b5\u4e0b\uff0c\u9664\u4e86CD8+ T\u7ec6\u80de\u4e4b\u5916\uff0c\u8fd8\u6709\u514d\u75ab\u6548\u5e94\u7ec6\u80de\u53c2\u4e0e\u3002\u63a5\u4e0b\u6765\uff0c\u6211\u4eec\u53d1\u73b0MMR-d\u80bf\u7624\u4e2dB2M\u5931\u6d3b\u548c\u03b3\u03b4 T\u7ec6\u80de\u6d78\u6da6\u589e\u52a0\u4e4b\u95f4\u7684\u5f3a\u5173\u8054\u3002\u8fd9\u4e9b\u03b3\u03b4 T\u7ec6\u80de\u4e3b\u8981\u7531V\u03b41\u548cV\u03b43\u4e9a\u7fa4\u7ec4\u6210\uff0c\u9ad8\u6c34\u5e73\u8868\u8fbePD-1\u3001\u5176\u4ed6\u6d3b\u5316\u6807\u5fd7\u7269(\u5305\u62ec\u7ec6\u80de\u6bd2\u6027\u5206\u5b50)\u548c\u5e7f\u6cdb\u7684\u6740\u4f24\u7ec6\u80de\u514d\u75ab\u7403\u86cb\u767d\u6837\u53d7\u4f53\u3002\u5728\u4f53\u5916\uff0c\u4eceMMR-d\u7ed3\u80a0\u764c\u4e2d\u5206\u79bb\u51fa\u7684PD-1+ \u03b3\u03b4 T\u7ec6\u80de\u5bf9\u4eba\u7c7b\u767d\u7ec6\u80de\u6297\u539f(HLA)-I\u9634\u6027\u7684MMR-d\u7ed3\u80a0\u764c\u7ec6\u80de\u7cfb\u548cb2m\u6572\u9664\u60a3\u8005\u6765\u6e90\u7684\u80bf\u7624\u7c7b\u5668\u5b98\u7684\u53cd\u5e94\u6027\u9ad8\u4e8e\u6297\u539f\u5448\u9012\u529f\u80fd\u6b63\u5e38\u7684\u7ec6\u80de\u3002\u901a\u8fc7\u6bd4\u8f83PD-1\u548cCTLA-4\u53cc\u91cd\u963b\u65ad\u4e4b\u524d\u548c\u4e4b\u540e\u83b7\u5f97\u7684MMR-d\u7ed3\u80a0\u764c\u60a3\u8005\u914d\u5bf9\u80bf\u7624\u6837\u672c\uff0c\u6211\u4eec\u53d1\u73b0\u514d\u75ab\u68c0\u67e5\u70b9\u963b\u65ad\u663e\u8457\u589e\u52a0\u4e86B2M\u7f3a\u9677\u764c\u75c7\u4e2d\u03b3\u03b4 T\u7ec6\u80de\u7684\u9891\u7387\u3002\u7efc\u4e0a\u6240\u8ff0\uff0c\u8fd9\u4e9b\u6570\u636e\u8868\u660e\uff0c\u03b3\u03b4 T\u7ec6\u80de\u6709\u52a9\u4e8eHLA-I\u9634\u6027MMR-d\u7ed3\u80a0\u764c\u60a3\u8005\u5bf9\u514d\u75ab\u68c0\u67e5\u70b9\u963b\u65ad\u7684\u5e94\u7b54\uff0c\u5e76\u5f3a\u8c03\u4e86\u03b3\u03b4 T\u7ec6\u80de\u5728\u764c\u75c7\u514d\u75ab\u6cbb\u7597\u4e2d\u7684\u6f5c\u529b\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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14<\/strong><\/p>\n<\/section>\n<\/section>\n

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Cell Res. 20230110<\/strong><\/p>\n<\/section>\n<\/section>\n

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Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria<\/strong><\/p>\n

\u9776\u5411ATAD3A-PINK1-\u7ebf\u7c92\u4f53\u81ea\u566c\u8f74\u901a\u8fc7\u5c06PD-L1\u91cd\u5b9a\u5411\u5230\u7ebf\u7c92\u4f53\u6765\u514b\u670d\u5316\u5b66\u514d\u75ab\u6cbb\u7597\u62b5\u6297<\/strong><\/span><\/p>\n


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Cell Res. 2023 Jan 10. <\/em><\/p>\n

doi: <\/strong>10.1038\/s41422-022-00766-z.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36627348\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1\/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.<\/p>\n

\u53ea\u6709\u5c11\u6570\u4e09\u9634\u6027\u4e73\u817a\u764c\u60a3\u8005\u53ef\u4ece\u9776\u5411PD-1\/PD-L1\u4fe1\u53f7\u7684\u514d\u75ab\u68c0\u67e5\u70b9\u6291\u5236\u5242(ICI)\u8054\u5408\u5316\u7597\u4e2d\u83b7\u76ca\u3002\u5728\u672c\u7814\u7a76\u4e2d\uff0c\u6211\u4eec\u53d1\u73b0ICI\u8054\u5408\u7d2b\u6749\u9187\u7684\u6cbb\u7597\u5e94\u7b54\u4e0ePD-L1\u7684\u4e9a\u7ec6\u80de\u518d\u5206\u5e03\u76f8\u5173\u3002\u5728\u6211\u4eec\u7684ICI\u8054\u5408nab-\u7d2b\u6749\u9187\u514d\u75ab\u6cbb\u7597\u961f\u5217\u4e2d\uff0c\u5e94\u7b54\u8005\u7684\u80bf\u7624\u6837\u672c\u663e\u793aPD-L1\u5728\u7ebf\u7c92\u4f53\u4e0a\u663e\u8457\u5206\u5e03\uff0c\u800c\u65e0\u5e94\u7b54\u8005\u7684\u80bf\u7624\u6837\u672c\u663e\u793aPD-L1\u5728\u80bf\u7624\u7ec6\u80de\u819c\u4e0a\u800c\u4e0d\u662f\u7ebf\u7c92\u4f53\u4e0a\u805a\u96c6\u589e\u52a0\u3002\u6211\u4eec\u7684\u7ed3\u679c\u8fd8\u8868\u660e\uff0cPD-L1\u7684\u5206\u5e03\u6a21\u5f0f\u53d7ATAD3A-PINK1\u8f74\u7684\u8c03\u8282\u3002\u673a\u5236\u4e0a\uff0cPINK1\u5c06PD-L1\u52df\u96c6\u5230\u7ebf\u7c92\u4f53\uff0c\u901a\u8fc7\u7ebf\u7c92\u4f53\u81ea\u566c\u9014\u5f84\u964d\u89e3\u3002\u91cd\u8981\u7684\u662f\uff0c\u7d2b\u6749\u9187\u901a\u8fc7\u6291\u5236PINK1\u4f9d\u8d56\u7684\u7ebf\u7c92\u4f53\u81ea\u566c\u6765\u589e\u52a0ATAD3A\u7684\u8868\u8fbe\uff0c\u4ece\u800c\u7834\u574fPD-L1\u7684\u7a33\u6001\u3002\u5728\u4e34\u5e8a\u4e0a\uff0cICI\u8054\u5408\u7d2b\u6749\u9187\u6cbb\u7597\u524dATAD3A\u9ad8\u8868\u8fbe\u60a3\u8005\u7684\u65e0\u8fdb\u5c55\u751f\u5b58\u671f\u660e\u663e\u77ed\u4e8eATAD3A\u4f4e\u8868\u8fbe\u60a3\u8005\u3002\u4e34\u5e8a\u524d\u7ed3\u679c\u8fdb\u4e00\u6b65\u8868\u660e\uff0c\u9776\u5411ATAD3A\u91cd\u5851\u4e86\u826f\u597d\u7684\u6297\u80bf\u7624\u514d\u75ab\u5fae\u73af\u5883\uff0c\u5e76\u63d0\u9ad8\u4e86ICI\u548c\u7d2b\u6749\u9187\u8054\u5408\u6cbb\u7597\u7684\u7597\u6548\u3002\u7efc\u4e0a\u6240\u8ff0\uff0c\u6211\u4eec\u7684\u7ed3\u679c\u8868\u660e\uff0cATAD3A\u4e0d\u4ec5\u53ef\u4ee5\u901a\u8fc7\u963b\u6b62PD-L1\u7ebf\u7c92\u4f53\u5206\u5e03\uff0c\u6210\u4e3aICI\u8054\u5408\u7d2b\u6749\u9187\u6cbb\u7597\u7684\u8010\u836f\u56e0\u7d20\uff0c\u800c\u4e14\u8fd8\u53ef\u4ee5\u4f5c\u4e3a\u589e\u52a0\u5316\u5b66\u514d\u75ab\u6cbb\u7597\u5e94\u7b54\u7684\u4e00\u4e2a\u6709\u524d\u666f\u7684\u9776\u70b9\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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15<\/strong><\/p>\n<\/section>\n<\/section>\n

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Nat Rev Cancer. 20230103<\/strong><\/p>\n<\/section>\n<\/section>\n

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STAT proteins in cancer: orchestration of metabolism<\/strong><\/p>\n

STAT\u86cb\u767d\u5728\u764c\u75c7\u4e2d\u7684\u4f5c\u7528\uff1a\u5bf9\u4ee3\u8c22\u7684\u8c03\u8282<\/strong><\/span><\/p>\n


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Nat Rev Cancer. 2023 Jan 3. <\/em><\/p>\n

doi: <\/strong>10.1038\/s41568-022-00537-3.<\/p>\n

PubMed: <\/strong>https:\/\/pubmed.ncbi.nlm.nih.gov\/36596870\/<\/span><\/p>\n


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Abstract<\/strong><\/span><\/p>\n

Reprogrammed metabolism is a hallmark of cancer. However, the metabolic dependency of cancer, from tumour initiation through disease progression and therapy resistance, requires a spectrum of distinct reprogrammed cellular metabolic pathways. These pathways include aerobic glycolysis, oxidative phosphorylation, reactive oxygen species generation, de novo lipid synthesis, fatty acid \u03b2-oxidation, amino acid (notably glutamine) metabolism and mitochondrial metabolism. This Review highlights the central roles of signal transducer and activator of transcription (STAT) proteins, notably STAT3, STAT5, STAT6 and STAT1, in orchestrating the highly dynamic metabolism not only of cancer cells but also of immune cells and adipocytes in the tumour microenvironment. STAT proteins are able to shape distinct metabolic processes that regulate tumour progression and therapy resistance by transducing signals from metabolites, cytokines, growth factors and their receptors; defining genetic programmes that regulate a wide range of molecules involved in orchestration of metabolism in cancer and immune cells; and regulating mitochondrial activity at multiple levels, including energy metabolism and lipid-mediated mitochondrial integrity. Given the central role of STAT proteins in regulation of metabolic states, they are potential therapeutic targets for altering metabolic reprogramming in cancer.<\/p>\n

\u4ee3\u8c22\u91cd\u7f16\u7a0b\u662f\u764c\u75c7\u7684\u4e00\u4e2a\u91cd\u8981\u6807\u5fd7\u3002\u7136\u800c\uff0c\u4ece\u80bf\u7624\u53d1\u751f\u5230\u75be\u75c5\u8fdb\u5c55\u548c\u8010\u836f\uff0c\u764c\u75c7\u7684\u4ee3\u8c22\u4f1a\u53d1\u751f\u4e00\u7cfb\u5217\u4e0d\u540c\u7684\u91cd\u7f16\u7a0b\u7ec6\u80de\u4ee3\u8c22\u9014\u5f84\u3002\u8fd9\u4e9b\u9014\u5f84\u5305\u62ec\u6709\u6c27\u7cd6\u9175\u89e3\u3001\u6c27\u5316\u78f7\u9178\u5316\u3001\u6d3b\u6027\u6c27\u751f\u6210\u3001\u8102\u8d28\u4ece\u5934\u5408\u6210\u3001\u8102\u80aa\u9178\u03b2-\u6c27\u5316\u3001\u6c28\u57fa\u9178(\u5c24\u5176\u662f\u8c37\u6c28\u9170\u80fa)\u4ee3\u8c22\u548c\u7ebf\u7c92\u4f53\u4ee3\u8c22\u3002\u8fd9\u7bc7\u7efc\u8ff0\u5f3a\u8c03\u4e86\u4fe1\u53f7\u8f6c\u5bfc\u548c\u8f6c\u5f55\u6fc0\u6d3b\u56e0\u5b50(STAT)\u86cb\u767d\uff0c\u5c24\u5176\u662fSTAT3, STAT5, STAT6\u548cSTAT1\uff0c\u5728\u534f\u8c03\u80bf\u7624\u7ec6\u80de\u3001\u514d\u75ab\u7ec6\u80de\u548c\u8102\u80aa\u7ec6\u80de\u5728\u80bf\u7624\u5fae\u73af\u5883\u4e2d\u7684\u9ad8\u5ea6\u52a8\u6001\u4ee3\u8c22\u4e2d\u7684\u6838\u5fc3\u4f5c\u7528\u3002STAT\u86cb\u767d\u80fd\u591f\u901a\u8fc7\u8f6c\u5bfc\u6765\u81ea\u4ee3\u8c22\u7269\u3001\u7ec6\u80de\u56e0\u5b50\u3001\u751f\u957f\u56e0\u5b50\u53ca\u5176\u53d7\u4f53\u7684\u4fe1\u53f7\u6765\u5f62\u6210\u8c03\u8282\u80bf\u7624\u8fdb\u5c55\u548c\u6cbb\u7597\u62b5\u6297\u7684\u72ec\u7279\u4ee3\u8c22\u8fc7\u7a0b\uff1b\u786e\u5b9a\u8c03\u8282\u53c2\u4e0e\u764c\u75c7\u548c\u514d\u75ab\u7ec6\u80de\u4ee3\u8c22\u91cd\u7f16\u7a0b\u7684\u5e7f\u6cdb\u5206\u5b50\u7684\u9057\u4f20\u7a0b\u5e8f\uff1b\u4ee5\u53ca\u5728\u591a\u4e2a\u6c34\u5e73\u8c03\u8282\u7ebf\u7c92\u4f53\u6d3b\u6027\uff0c\u5305\u62ec\u80fd\u91cf\u4ee3\u8c22\u548c\u8102\u8d28\u4ecb\u5bfc\u7684\u7ebf\u7c92\u4f53\u5b8c\u6574\u6027\u3002\u9274\u4e8eSTAT\u86cb\u767d\u5728\u4ee3\u8c22\u72b6\u6001\u8c03\u8282\u4e2d\u7684\u6838\u5fc3\u4f5c\u7528\uff0c\u5b83\u4eec\u662f\u6539\u53d8\u764c\u75c7\u4e2d\u4ee3\u8c22\u91cd\u7f16\u7a0b\u7684\u6f5c\u5728\u6cbb\u7597\u9776\u70b9\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n

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\u8be5\u661f\u7403\u7528\u4e8eOncoLab\u516c\u4f17\u53f7\u8bfb\u8005\u4ea4\u6d41\u5b66\u4e60\u4f7f\u7528\uff0c\u6c38\u4e45\u514d\u8d39<\/span>\u3002<\/span><\/span><\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n

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