Combination anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti–programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8⁺ and CD4⁺ T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti–CTLA-4, anti–PD-1, or combination therapy. Most (>50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of HLA-A, HLA-B, HLA-C, and B2M, and predicted primary resistance to anti–CTLA-4, but not anti–PD-1, therapy. Melanoma MHC class II membrane expression on >1% cells was observed in 55 of 181 cases (30%), was associated with interferon-γ (IFN-γ) and IFN-γ–mediated gene signatures, and predicted response to anti–PD-1, but not anti–CTLA-4, therapy. We conclude that primary response to anti–CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti–PD-1 is associated with preexisting IFN-γ–mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity.

与单独治疗相比，抗细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 和抗程序性细胞死亡蛋白 1 (PD-1) 联合治疗可促进抗肿瘤免疫并为晚期黑色素瘤患者提供更好的益处。T 细胞免疫需要在主要组织相容性复合体 (MHC) I 类和 II 类蛋白的背景下通过 CD8 ⁺和 CD4 ⁺识别抗原T 细胞，分别。我们检查了来自先前未治疗的黑色素瘤患者的肿瘤细胞上的 MHC I 类和 II 类蛋白表达，并将结果与​​转录和基因组分析以及抗 CTLA-4、抗 PD-1 或​​联合治疗的临床反应相关联。在 181 例病例中的 78 例（43%）中观察到大多数（>50% 的细胞）或完全丧失黑色素瘤 MHC I 类膜表达，这与HLA-A、HLA-B、HLA-C和B2M 的转录抑制有关，并预测了对抗 CTLA-4 而非抗 PD-1 治疗的原发性耐药。在 181 例病例中的 55 例（30%）中观察到 >1% 细胞上的黑色素瘤 MHC II 类膜表达，与干扰素-γ（IFN-γ）和 IFN-γ 介导的基因特征相关，并预测对抗 PD 的反应-1，但不是抗 CTLA-4 疗法。我们得出结论，对抗 CTLA-4 的主要反应需要强大的黑色素瘤 MHC I 类表达。相比之下，抗 PD-1 的主要反应与预先存在的 IFN-γ 介导的免疫激活相关，包括肿瘤特异性 MHC II 类表达和 MHC I 类受损时的先天免疫成分。联合检查点阻断的好处可能部分归因于对黑色素瘤特异性抗原呈递以启动抗肿瘤免疫的不同要求。