Biomarkers of response and resistance to checkpoint blockade immunotherapy in metastatic melanoma

Identifying the mechanistic features that determine a cancer patient's response to immune checkpoint inhibitors is a critical step towards improving the efficacy of current therapies and optimising the design of clinical trials for next-generation drugs. Here, we investigated the transcriptomic and immunophenotypic profiles of metastatic melanoma patients treated with anti-PD-1 alone or combined anti-PD-1 and anti-CTLA-4 immunotherapy. Effector T-cells are essential for increased anti-cancer activity, favouring better survival outcomes in patients treated with anti-PD-1 monotherapy. In contrast, response to combined anti-PD-1 and anti-CTLA-4 immunotherapy relied upon memory cytotoxic and helper T-cell populations. Patients with resistance to immune checkpoint blockade exploited the metabolic and hypoxia-mediated pathways to alter tumour microenvironment causing impairment of T-cell trafficking and function. Our findings provide a strong rationale for stratifying patients based on molecular profiles that determine response and resistance to anti-PD1 alone or in combination with anti-CTLA-4 immunotherapy.