BCL2 Inhibition Reveals a Dendritic Cell-Specific Immune Checkpoint That Controls Tumor Immunosurveillance.
BCL2 Inhibition Reveals a Dendritic Cell-Specific Immune Checkpoint That Controls Tumor Immunosurveillance.
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DOI：
10.1158/2159-8290.cd-22-1338
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发表时间：
2023-11-01
期刊：
影响因子：
28.2
通讯作者：
Kroemer G
中科院分区：
文献类型：
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作者：
Zhao L;Liu P;Mao M;Zhang S;Bigenwald C;Dutertre CA;Lehmann CHK;Pan H;Paulhan N;Amon L;Buqué A;Yamazaki T;Galluzzi L;Kloeckner B;Silvin A;Pan Y;Chen H;Tian AL;Ly P;Dudziak D;Zitvogel L;Kepp O;Kroemer G
我们开发了一个用于树突状细胞（DC）功能研究的表型筛选平台。在这里，我们报告了一个全基因组CRISPR筛选，揭示了BCL 2作为DC功能的内源性抑制剂。BCL 2的敲除增强DC抗原呈递和活化以及DC控制肿瘤和与PD-1阻断协同的能力。药理学BCL 2抑制剂venetoclax和navitoclax表型模仿这些作用，并导致原位肺癌和纤维肉瘤的cDC 1依赖性消退。因此，实体瘤未能响应Bcl 2抑制在小鼠组成性缺乏cDC 1，这是逆转的DC输注。此外，cDC 1消耗降低了BCL 2抑制剂单独或与PD-1阻断剂联合使用的治疗效果，并且在小鼠和患者中，用维奈托克治疗引起cDC 1激活。总之，遗传和药理学BCL 2抑制揭示了抑制肿瘤免疫监视的DC特异性免疫检查点。
We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacological BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to Bcl2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacological BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance.