Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients.,Since most patients do not respond, predictive biomarkers to guide treatment selection are needed.,We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response.,In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous.,A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions.,Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of ‘PD-1 signalling', ‘allograft rejection' and ‘T-cell receptor signalling', among others.,In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4+ and CD8+ tumour infiltrate.,MHC-II+ tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.,Immunotherapy is used to treat melanoma, however patient responses vary widely highlighting the need for factors that can predict therapeutic success.,Here, the authors show that MHC-II molecules expressed by tumour cells are positively correlated with a good response to therapy and overall patient survival.
Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear1,2.,The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event3.,To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a V600EBRAF mouse model.,In mice expressing V600EBRAF in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden.,We show that sunscreen (UVA superior: UVB SPF50) delayed the onset of UVR-driven melanoma, but only provided partial protection.,The UVR-exposed tumours presented increased numbers of single nucleotide variants (SNVs) and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in ~40% of cases.,TP53 is an accepted UVR target in non-melanoma skin cancer, but is not thought to play a major role in melanoma4.,However, we show that mutant Trp53 accelerated V600EBRAF-driven melanomagenesis and that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma.,Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans5.,We identify TP53/Trp53 as a UVR-target gene that cooperates with V600EBRAF to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis.,Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.