Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis.
Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis.
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DOI：
10.1158/0008-5472.can-13-3596
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发表时间：
2014-07-01
期刊：
影响因子：
11.2
通讯作者：
Zhou G
中科院分区：
文献类型：
--
作者：
Ding ZC;Lu X;Yu M;Lemos H;Huang L;Chandler P;Liu K;Walters M;Krasinski A;Mack M;Blazar BR;Mellor AL;Munn DH;Zhou G
近年来，基于免疫的疗法已成为癌症患者越来越有吸引力的治疗选择。癌症免疫疗法通常与常规化疗联合使用以产生协同效应。由于其众所周知的免疫刺激作用，烷化剂环磷酰胺（CTX）已被包括在各种化学免疫治疗方案中。巧合的是，CTX也可以诱导抑制免疫反应的抑制细胞。然而，这些抑制细胞的身份和生物学相关性很难定义。在这里，我们报告说，CTX治疗驱动具有免疫抑制活性的炎性单核细胞骨髓细胞（CD 11b + Ly 6ChiCCR 2 hi）的扩增。在患有晚期淋巴瘤的小鼠中，CTX治疗后肿瘤特异性CD 4 + T细胞的过继转移（AT）（CTX+ CD 4 AT）引起了强烈的初始抗肿瘤免疫应答，但也导致单核细胞骨髓细胞扩增增强。这些治疗诱导的单核细胞通过PD-1/PD-L1轴介导抗肿瘤CD 4+效应细胞的功能耐受化，抑制长期肿瘤控制并允许随后复发。CTX+ CD 4 AT治疗后的PD-1/PD-L1阻断导致CD 4+效应细胞的持续存在和持久的抗肿瘤作用。通过给予低剂量吉西他滨消耗增殖单核细胞有效地预防了CTX+ CD 4 AT治疗后的肿瘤复发。同样，通过破坏CCR 2信号通路靶向炎性单核细胞显著增强了基于CTX的治疗的功效。除了CTX外，我们发现美法仑和阿霉素也可以诱导单核细胞骨髓抑制细胞。这些发现揭示了某些化疗药物引起的反调节机制，并强调了克服这一障碍以防止化学免疫治疗后晚期肿瘤复发的重要性。
In recent years, immune-based therapies have become an increasingly attractive treatment option for patients with cancer. Cancer immunotherapy is often used in combination with conventional chemotherapy for synergistic effects. The alkylating agent cyclophosphamide (CTX) has been included in various chemoimmunotherapy regimens due to its well-known immunostimulatory effects. Paradoxically, CTX can also induce suppressor cells that inhibit immune responses. However, the identity and biological relevance of these suppressor cells are poorly defined. Here we report that CTX treatment drives the expansion of inflammatory monocytic myeloid cells (CD11b+Ly6ChiCCR2hi) that possess immunosuppressive activities. In mice with advanced lymphoma, adoptive transfer (AT) of tumor-specific CD4+ T cells following CTX treatment (CTX+CD4 AT) provoked a robust initial antitumor immune response, but also resulted in enhanced expansion of monocytic myeloid cells. These therapy-induced monocytes inhibited long-term tumor control and allowed subsequent relapse by mediating functional tolerization of antitumor CD4+ effector cells through the PD-1/PD-L1 axis. PD-1/PD-L1 blockade after CTX+CD4 AT therapy led to persistence of CD4+ effector cells and durable antitumor effects. Depleting proliferative monocytes by administering low dose gemcitabine effectively prevented tumor recurrence after CTX+CD4 AT therapy. Likewise, targeting inflammatory monocytes by disrupting the CCR2 signaling pathway markedly potentiated the efficacy of CTX-based therapy. Besides CTX, we found that melphalan and doxorubicin can also induce monocytic myeloid suppressor cells. These findings reveal a counter-regulation mechanism elicited by certain chemotherapeutic agents, and highlight the importance of overcoming this barrier to prevent late tumor relapse after chemoimmunotherapy.