Macquarie University, Sydney, NSW, Australia.
Melanoma Institute Australia, Sydney, NSW, Australia.
Nat Commun. 2020 Apr 20;11(1):1897. doi: 10.1038/s41467-020-15726-7.
Transcriptomic signatures designed to predict melanoma patient responses to PD-1 blockade have been reported but rarely validated. We now show that intra-patient heterogeneity of tumor responses to PD-1 inhibition limit the predictive performance of these signatures. We reasoned that resistance mechanisms will reflect the tumor microenvironment, and thus we examined PD-1 inhibitor resistance relative to T-cell activity in 94 melanoma tumors collected at baseline and at time of PD-1 inhibitor progression. Tumors were analyzed using RNA sequencing and flow cytometry, and validated functionally. These analyses confirm that major histocompatibility complex (MHC) class I downregulation is a hallmark of resistance to PD-1 inhibitors and is associated with the MITF/AXL de-differentiated phenotype and cancer-associated fibroblast signatures. We demonstrate that TGFß drives the treatment resistant phenotype (MITF/AXL) and contributes to MHC class I downregulation in melanoma. Combinations of anti-PD-1 with drugs that target the TGFß signaling pathway and/or which reverse melanoma de-differentiation may be effective future therapeutic strategies.
已有报道称，转录组特征可预测黑色素瘤患者对 PD-1 阻断的反应，但很少得到验证。我们现在表明，肿瘤对 PD-1 抑制的反应的患者内异质性限制了这些特征的预测性能。我们推断，耐药机制将反映肿瘤微环境，因此我们在 94 个黑色素瘤肿瘤中检查了 PD-1 抑制剂进展时的基线和 T 细胞活性相对的 PD-1 抑制剂耐药性。使用 RNA 测序和流式细胞术对肿瘤进行分析，并进行了功能验证。这些分析证实，主要组织相容性复合体 (MHC) Ⅰ类下调是对 PD-1 抑制剂耐药的标志，与 MITF/AXL 去分化表型和癌症相关成纤维细胞特征相关。我们证明 TGFβ 驱动治疗耐药表型（MITF/AXL），并导致黑色素瘤中 MHC Ⅰ类下调。抗 PD-1 与靶向 TGFβ 信号通路的药物联合使用，或逆转黑色素瘤去分化的药物，可能是未来有效的治疗策略。
