Proteomics of melanoma response to immunotherapy reveals dependence on mitochondrial function

Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by deeply profiling the proteome of clinical samples from advanced stage melanoma patients undergoing either tumor infiltrating lymphocytes (TIL)-based or anti-PD1 immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins with high accuracy. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders in both treatments, and identified proteomic signatures for response. Aiming to elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or Crisp-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby affecting the sensitivity to T-cell mediated killing both in-vitro and in-vivo. Altogether, our proteomic analyses revealed novel association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.