循环单核细胞与人类胆道癌抗 PD-1 耐药相关，可诱导 T 细胞衰竭。
Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis.
机构信息
Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA; Cancer Immunotherapy Program, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
出版信息
Cell Rep. 2022 Sep 20;40(12):111384. doi: 10.1016/j.celrep.2022.111384.
Suppressive myeloid cells can contribute to immunotherapy resistance, but their role in response to checkpoint inhibition (CPI) in anti-PD-1 refractory cancers, such as biliary tract cancer (BTC), remains elusive. We use multiplexed single-cell transcriptomic and epitope sequencing to profile greater than 200,000 peripheral blood mononuclear cells from advanced BTC patients (n = 9) and matched healthy donors (n = 8). Following anti-PD-1 treatment, CD14 monocytes expressing high levels of immunosuppressive cytokines and chemotactic molecules (CD14) increase in the circulation of patients with BTC tumors that are CPI resistant. CD14 can directly suppress CD4 T cells and induce SOCS3 expression in CD4 T cells, rendering them functionally unresponsive. The CD14 gene signature associates with worse survival in patients with BTC as well as in other anti-PD-1 refractory cancers. These results demonstrate that monocytes arising after anti-PD-1 treatment can induce T cell paralysis as a distinct mode of tumor-mediated immunosuppression leading to CPI resistance.
抑制性髓系细胞可能导致免疫疗法耐药，但它们在抗 PD-1 难治性癌症（如胆道癌 (BTC)）中对检查点抑制 (CPI) 的反应中的作用仍不清楚。我们使用多重单细胞转录组和表位测序技术，对 9 名晚期 BTC 患者和 8 名匹配的健康供体的超过 200,000 个外周血单核细胞进行了分析。在接受抗 PD-1 治疗后，在对 CPI 耐药的 BTC 肿瘤患者的循环中，高水平表达免疫抑制细胞因子和趋化分子的 CD14 单核细胞（CD14）增加。CD14 可以直接抑制 CD4 T 细胞，并诱导 CD4 T 细胞中 SOCS3 的表达，使它们失去功能反应性。CD14 基因特征与 BTC 患者以及其他抗 PD-1 难治性癌症患者的生存不良相关。这些结果表明，抗 PD-1 治疗后出现的单核细胞可以诱导 T 细胞瘫痪，作为一种导致 CPI 耐药的肿瘤介导免疫抑制的独特模式。
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