在黑色素瘤中，免疫检查点抑制剂治疗的耐药性很常见，并且仍是一项难以解决的临床挑战。在本研究中，我们全面分析了短期肿瘤细胞系和黑色素瘤患者进展期的匹配肿瘤样本中免疫检查点抑制剂耐药机制。通过基因组、转录组和高维流式细胞术分析及功能分析相结合，我们确定了三种不同的免疫疗法耐药程序。在这里，我们展示了耐药程序包括(1)野生型抗原表达的丧失，由于肿瘤内在的IFNγ信号和黑色素瘤去分化引起，(2)通过影响MHC表达的多个独立机制破坏抗原呈递，以及(3)伴随PTEN丧失的免疫细胞排除。抗原生产和呈递受损在黑色素瘤耐抗免疫检查点抑制中的占主导地位，突出了针对MHC表达恢复、促进先天免疫和重表达野生型分化抗原的治疗挽救策略的重要性。©2023.作者。

Resistance to immune checkpoint inhibitor therapies in melanoma is common and remains an intractable clinical challenge. In this study, we comprehensively profile immune checkpoint inhibitor resistance mechanisms in short-term tumor cell lines and matched tumor samples from melanoma patients progressing on immune checkpoint inhibitors. Combining genome, transcriptome, and high dimensional flow cytometric profiling with functional analysis, we identify three distinct programs of immunotherapy resistance. Here we show that resistance programs include (1) the loss of wild-type antigen expression, resulting from tumor-intrinsic IFNγ signaling and melanoma de-differentiation, (2) the disruption of antigen presentation via multiple independent mechanisms affecting MHC expression, and (3) immune cell exclusion associated with PTEN loss. The dominant role of compromised antigen production and presentation in melanoma resistance to immune checkpoint inhibition highlights the importance of treatment salvage strategies aimed at the restoration of MHC expression, stimulation of innate immunity, and re-expression of wild-type differentiation antigens.© 2023. The Author(s).