Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, 02114, USA.
Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA.
Nat Commun. 2017 Oct 26;8(1):1136. doi: 10.1038/s41467-017-01062-w.
Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (30%) compared to responders (10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.
免疫检查点阻断（CPB）治疗通常可使转移性黑色素瘤患者获得长期缓解，但这些药物发生原发性和获得性耐药的常见机制仍不完全明确，且尚未在大样本队列中得到验证。通过分析 17 名接受 CPB 治疗的转移性黑色素瘤患者的纵向肿瘤活检样本，我们在疾病进展患者中观察到 29.4%存在 MHC Ⅰ类抗原呈递必需成分β2-微球蛋白（B2M）的点突变、缺失或杂合性丢失（LOH）。在分别接受抗 CTLA4 和抗 PD1 治疗的黑色素瘤患者的两个独立队列中，我们发现 B2M LOH 在无应答者（30%）中富集了三倍，而在有应答者（10%）中富集了三倍，且与总生存期较差相关。仅在无应答者中发现 B2M 的两个拷贝均丢失。B2M 的丢失可能是针对 CTLA4 或 PD1 的治疗发生耐药的常见机制。
