Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy
Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy
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DOI：
10.1016/j.immuni.2017.09.012
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发表时间：
2017-10-17
期刊：
影响因子：
32.4
通讯作者：
Hoelzel, Michael
中科院分区：
文献类型：
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作者：
Glodde, Nicole;Bald, Tobias;Hoelzel, Michael
受体酪氨酸激酶c-met的抑制剂目前在临床上用于靶向肿瘤细胞中的致癌信号。我们发现，伴随的c-met抑制通过增加肿瘤中效应T细胞的渗透，促进了过继T细胞转移和小鼠癌症模型中的检查点免疫治疗。这种治疗效果不依赖于肿瘤细胞固有的c-met依赖。从机制上讲，c-met的抑制作用削弱了中性粒细胞对细胞毒免疫治疗的反应性动员和募集到肿瘤和引流淋巴结的反应。在没有c-met抑制的情况下，中性粒细胞被招募到T细胞炎症的微环境中，迅速获得免疫抑制特性，抑制T细胞的扩张和效应功能。在癌症患者中，血清c-met配体HGF水平高与中性粒细胞计数增加和对检查点阻断治疗的反应差相关。我们的发现揭示了HGF/c-Met途径在中性粒细胞募集和功能中的作用，并表明c-Met抑制剂联合治疗可能会改善c-Met依赖肿瘤以外的环境中对癌症免疫治疗的反应。
Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition, neutrophils recruited to T cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T cell expansion and effector functions. In cancer patients, high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts and poor responses to checkpoint blockade therapies. Our findings reveal a role for the HGF/c-MET pathway in neutrophil recruitment and function and suggest that c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors.