National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
Danish Cancer Society Research Center, Copenhagen, Denmark.
Cancer Immunol Res. 2022 Oct 4;10(10):1254-1262. doi: 10.1158/2326-6066.CIR-22-0326.
Responses to immunotherapy can be very durable but acquired resistance leading to tumor progression often occurs. We investigated a patient with melanoma resistant to anti-programmed death 1 (anti-PD-1) who participated in the CA224-020 clinical trial (NCT01968109) and had further progression after an initial objective response to anti-PD-1 plus anti-lymphocyte activation gene 3. We found consecutive acquisition of beta-2 microglobulin (B2M) loss and impaired Janus kinase 1 (JAK1) signaling that coexisted in progressing tumor cells. Functional analyses revealed a pan T-cell immune escape phenotype, where distinct alterations mediated independent immune resistance to tumor killing by autologous CD8+ tumor-infiltrating lymphocytes (TIL; B2M loss) and CD4+ TILs (impaired JAK1 signaling). These findings shed light on the complexity of acquired resistance to immunotherapy in the post anti-PD-1 setting, indicating that coexisting altered pathways can lead to pan T-cell immune escape.
免疫治疗的反应可能非常持久，但获得性耐药导致肿瘤进展常常发生。我们研究了一名对抗程序性死亡 1（抗 PD-1）耐药的黑色素瘤患者，该患者参与了 CA224-020 临床试验（NCT01968109），并在抗 PD-1 联合抗淋巴细胞激活基因 3 初始客观反应后进一步进展。我们发现进展中的肿瘤细胞连续获得β-2 微球蛋白（B2M）缺失和 Janus 激酶 1（JAK1）信号受损，这两种情况同时存在。功能分析显示出一种全 T 细胞免疫逃逸表型，其中不同的改变介导了对自体 CD8+肿瘤浸润淋巴细胞（TIL；B2M 缺失）和 CD4+TIL 杀伤肿瘤的独立免疫耐药（JAK1 信号受损）。这些发现揭示了抗 PD-1 后免疫治疗获得性耐药的复杂性，表明共存的改变途径可能导致全 T 细胞免疫逃逸。
