Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.
Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer 5265601, Israel; Department of Clinical Immunology and Microbiology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.
Cell. 2019 Sep 19;179(1):236-250.e18. doi: 10.1016/j.cell.2019.08.012. Epub 2019 Sep 5.
Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by profiling the proteome of clinical samples from advanced stage melanoma patients undergoing either tumor infiltrating lymphocyte (TIL)-based or anti- programmed death 1 (PD1) immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins in total and ∼4,500 proteins across most samples in each dataset. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders than in non-responders in both treatments. To elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or CRISPR-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby increasing sensitivity to T cell mediated killing both in vitro and in vivo. Altogether, our proteomic analyses revealed association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.
免疫疗法已经彻底改变了癌症治疗，然而大多数患者对此没有反应。在这里，我们通过对接受肿瘤浸润淋巴细胞（TIL）或抗程序性死亡 1（PD1）免疫疗法的晚期黑色素瘤患者的临床样本进行蛋白质组学分析，研究了反应的机制。我们使用高分辨率质谱法，在每个数据集的大多数样本中总共定量了超过 10300 种蛋白质和约 4500 种蛋白质。统计分析表明，两种治疗方法中，应答者的氧化磷酸化和脂质代谢水平均高于无应答者。为了阐明代谢状态对免疫反应的影响，我们在代谢扰动或 CRISPR-Cas9 敲除后检查了黑色素瘤细胞。这些实验表明，脂质代谢是一种调节机制，通过增加抗原呈递来提高黑色素瘤的免疫原性，从而增加体外和体内对 T 细胞介导杀伤的敏感性。总之，我们的蛋白质组学分析揭示了黑色素瘤代谢状态与免疫疗法反应之间的关联，这可能为未来改善治疗反应提供基础。
