Correlates of metastatic melanoma response to checkpoint inhibition

Immunotherapy for metastatic melanoma has a decades-long history, and the relatively recent use of checkpoint inhibitors has revolutionized treatment. Durable, and sometimes complete, remission of metastatic melanoma is now achievable in some patients receiving checkpoint-blocking therapy. However, it is unclear why some patients fare better than others. This review highlights several molecular indicators of response to checkpoint inhibition in metastatic melanoma, focusing on tumor PDL1 expression, MHC I expression, mutational load in the tumor, and T cell infiltration in the tumor. Additionally, clinical correlates of response, notably vitiligo and other immune-related adverse events, can potentially shed light on the mechanisms by which checkpoint blockade may achieve such great success, particularly in melanoma. We propose that MITF – a key regulator of melanocyte survival, melanin production, and melanoma transformation – produces a molecular landscape in melanocytes and melanoma cells that can make melanomas particularly susceptible to checkpoint blockade and also that can also result in immune attack on normal melanocytes.