Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling
Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling
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DOI：
10.1158/0008-5472.can-16-3172
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发表时间：
2017-09-01
期刊：
影响因子：
11.2
通讯作者：
Svane, Inge Marie
中科院分区：
文献类型：
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作者：
Donia, Marco;Harbst, Katja;Svane, Inge Marie
癌症免疫疗法可以在一些患者中导致持久的肿瘤消退。然而，最初有反应的患者往往会经历肿瘤进展。在这里，我们报告了一个典型的临床病例中肿瘤免疫逃逸的机制证据：一个转移性黑色素瘤患者在基于T细胞的免疫治疗后，在最初的、明确的放射学完全消退后出现疾病复发。功能性细胞毒性T细胞应答，包括对一种突变新抗原的应答，通过治疗有效扩增，并产生持久的免疫记忆。然而，这些免疫反应，包括对肿瘤突变组的明显有效的监视，并不能防止复发。耐药癌细胞中MHC I类抗原加工和呈递机制（APM）的改变，而不是抗原丢失或IFN γ信号转导受损，导致肿瘤特异性CD8（+）T细胞的识别受损。我们的研究结果表明，未来的免疫治疗组合应考虑靶向具有完整和受损的MHC I类相关APM的癌细胞。靶抗原丢失或IFN γ信号传导受损似乎不是肿瘤完全消退后复发的必要因素。需要进行个性化研究，以揭示导致每个患者疾病复发的机制。(C)2017年AACR。
Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell-based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFN gamma signaling, led to impaired recognition by tumor-specific CD8(+) T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I-related APM. Loss of target antigens or impaired IFN gamma signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted. (C) 2017 AACR.