Lim Su Yin, Alavi Sara, Ming Zizhen, Shklovskaya Elena, Fung Carina, Stewart Ashleigh, Rizos Helen
Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia.
Melanoma Institute Australia, Sydney, NSW 2065, Australia.
Biomedicines. 2021 May 26;9(6):605. doi: 10.3390/biomedicines9060605.
Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD1) pathway have revolutionized the treatment of patients with advanced metastatic melanoma. PD1 inhibitors reinvigorate exhausted tumor-reactive T cells, thus restoring anti-tumor immunity. Tumor necrosis factor alpha (TNFα) is abundantly expressed as a consequence of T cell activation and can have pleiotropic effects on melanoma response and resistance to PD1 inhibitors. In this study, we examined the influence of TNFα on markers of melanoma dedifferentiation, antigen presentation and immune inhibition in a panel of 40 melanoma cell lines. We report that TNFα signaling is retained in all melanomas but the downstream impact of TNFα was dependent on the differentiation status of melanoma cells. We show that TNFα is a poor inducer of antigen presentation molecules HLA-ABC and HLA-DR but readily induces the PD-L2 immune checkpoint in melanoma cells. Our results suggest that TNFα promotes dynamic changes in melanoma cells that may favor immunotherapy resistance.
靶向程序性细胞死亡蛋白1（PD1）通路的免疫检查点抑制剂彻底改变了晚期转移性黑色素瘤患者的治疗方式。PD1抑制剂可使耗竭的肿瘤反应性T细胞恢复活力，从而恢复抗肿瘤免疫力。肿瘤坏死因子α（TNFα）作为T细胞激活的结果大量表达，并且对黑色素瘤对PD1抑制剂的反应和耐药性可能具有多效性影响。在本研究中，我们在一组40个黑色素瘤细胞系中研究了TNFα对黑色素瘤去分化、抗原呈递和免疫抑制标志物的影响。我们报告称，TNFα信号在所有黑色素瘤中均存在，但TNFα的下游影响取决于黑色素瘤细胞的分化状态。我们表明，TNFα是抗原呈递分子HLA-ABC和HLA-DR的低效诱导剂，但很容易在黑色素瘤细胞中诱导PD-L2免疫检查点。我们的结果表明，TNFα促进黑色素瘤细胞的动态变化，这可能有利于免疫治疗耐药性。
