Proteomics of melanoma response to immunotherapy reveals mitochondrial dependence
February 9, 2020
One of the urgent questions in medicine is to understand why specific treatment helps tremendously to one patient but not to another? This question becomes even more complex when heterogeneity of tumor progression itself is involved. The team of Prof. Tami Geiger from the Tel Aviv University in collaboration with Prof. Gal Markel and Sheba's Ella Lemelbaum Institute for Immuno-Oncology addressed this question by conducting an extensive and systematic analysis of 116 clinical samples taken from advanced-stage melanoma patients when half of them responded to the immunotherapy treatment and half not. In a study of melanoma, Dr. Michal Harel with colleagues identified proteomic signatures that predict response to immunotherapy. Quantification of more than 10,000 proteins by high-resolution mass spectrometry, followed by extensive bioinformatic analysis revealed higher oxidative phosphorylation and lipid metabolism in responders in both treatments. Metabolic and genetic perturbations using Crispr-Cas9 technology indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby increasing sensitivity to T-cell mediated killing both in-vitro and in-vivo. These analyses revealed a novel association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response. This study shows the importance of examining the protein level, to reveal novel functional associations, as the basis of future drug development.