Bacterial immunotherapy for cancer induces CD4-dependent tumor-specific immunity through tumor-intrinsic interferon-γ signaling
Bacterial immunotherapy for cancer induces CD4-dependent tumor-specific immunity through tumor-intrinsic interferon-γ signaling
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DOI：
10.1073/pnas.2004421117
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发表时间：
2020-08-04
影响因子：
11.1
通讯作者：
Redelman-Sidi, Gil
中科院分区：
文献类型：
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作者：
Antonelli, Anthony C.;Binyamin, Anna;Redelman-Sidi, Gil
卡介苗（BCG）免疫治疗膀胱癌是唯一被批准用于临床的细菌癌症治疗。虽然推测诱导T细胞介导的免疫，肿瘤消除是否取决于细菌特异性或肿瘤特异性免疫是未知的。在本文中，我们表明，BCG诱导的膀胱肿瘤消除需要CD 4和CD 8 T细胞，尽管细菌抗原特异性T细胞反应的增强或抑制不会改变BCG诱导的肿瘤消除的功效。相比之下，BCG刺激主要依赖于CD 4 T细胞的长期肿瘤特异性免疫。我们证明，BCG治疗导致肿瘤特异性CD 4 T细胞的效应子功能增强，主要是通过增强IFN-γ的产生。因此，BCG诱导的肿瘤消除和肿瘤特异性免疫记忆需要肿瘤细胞表达IFN-γ受体，而不是MHC II类。我们的研究结果证实，用于癌症的细菌免疫疗法能够诱导肿瘤免疫，这是一种由肿瘤特异性CD 4 T细胞功能增强引起的抗肿瘤作用，并最终需要肿瘤内在IFN-γ信号传导，其机制与其他肿瘤免疫疗法不同。
Bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer is the only bacterial cancer therapy approved for clinical use. Although presumed to induce T cell-mediated immunity, whether tumor elimination depends on bacteria-specific or tumor-specific immunity is unknown. Herein we show that BCG-induced bladder tumor elimination requires CD4 and CD8 T cells, although augmentation or inhibition of bacterial antigen-specific T cell responses does not alter the efficacy of BCG-induced tumor elimination. In contrast, BCG stimulates long-term tumor-specific immunity that primarily depends on CD4 T cells. We demonstrate that BCG therapy results in enhanced effector function of tumor-specific CD4 T cells, mainly through enhanced production of IFN-gamma. Accordingly, BCG-induced tumor elimination and tumor-specific immune memory require tumor cell expression of the IFN-gamma receptor, but not MHC class II. Our findings establish that a bacterial immunotherapy for cancer is capable of inducing tumor immunity, an antitumor effect that results from enhanced function of tumor-specific CD4 T cells, and ultimately requires tumor-intrinsic IFN-gamma signaling, via a mechanism that is distinct from other tumor immunotherapies.