Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.

中文翻译：

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从I类HLA的转录缺失获得了对联合免疫疗法的抗癌性。

了解晚期/后天癌症免疫治疗耐药性的机制对于改善结局至关重要。细胞免疫疗法试验提供了一种通过定义的T细胞/抗原相互作用探测复杂的肿瘤-免疫界面的方法。我们用自体默克尔细胞多瘤病毒特异性CD8 + T细胞和免疫检查点抑制剂治疗了两名转移性默克尔细胞癌患者。在这两种情况下，戏剧性的缓解都与活化的CD8 + s向浸润性肿瘤的密集浸润有关。但是，晚期复发分别发生在22和18个月。在这里，我们报告单细胞RNA测序鉴定了由于强烈的CD8介导的免疫学压力而在耐药性肿瘤中呈现靶向病毒表位的特定HLA基因的动态转录抑制；这与遗传性HLA丢失的区别在于其与药物的可逆性。I类基因座的转录抑制可能是对其他免疫疗法（包括检查点抑制剂）的抵抗力的基础，对改进免疫疗法的设计具有影响。