Abstract 1892: Proteomic interrogation of the metabolic control of MHC class I antigen presentation in metastatic melanoma

Abstract

Abstract Since 2014, immune checkpoint inhibitors (ICIs) have led the charge against metastatic melanoma as the most commonly utilized first-line treatment. While ICIs have dramatically increased the 5-year overall survival rate, only half of patients respond to treatment. Recently, a proteomic study correlated high levels of tumor mitochondrial metabolic proteins and MHC-related proteins to responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitor treatment. In a study of 91 melanoma cell lines in the European Searchable Tumor Cell and Databank, 67% of the cell lines exhibited HLA class antigen alterations, most commonly being down-regulation of HLA-B. Loss of MHC expression is a mechanism proposed to aid in evading the immune system by decreasing T-cell recognition and killing. Approaches to reverse tumor MHC loss is needed as it is a known mechanism utilized by melanoma and increased MHC expression has been linked to ICI responders. The connection between metabolism and MHC correlation has not been fully explored, and this study sought to further explore that relationship through a proteomic analysis of a metabolically conditioned B16F10 murine melanoma model. To expand our understanding of the metabolic control of MHC Class I antigen presentation, we cultured B16F10 melanoma cells in galactose media (B16.Gal), forcing the cells into an oxidative phosphorylative state relative to B16F10 melanoma cells cultured in glucose media (B16.Glu) which exhibit a glycolytic metabolic profile. We show that enforcing mitochondrial respiration restores the lost basal MHC expression and enhances the response to interferon gamma. Further, B16.Gal cells show higher rates of T-cell killing and increased PD-L1 expression. This phenotype proved reversible as shown by moving B16.Gal cells back into glucose media (B16.GalGlu), supporting the formation of a metabolically conditioned cell model rather than a favorable selection of compatible cells. We used proteomics to identify the driving forces behind the restoration of MHC expression. The identification of these forces could provide novel therapeutic targets for enhancing immunotherapy of melanoma. Citation Format: Alyson McKinnon, Nathan Avaritt, Alan Tackett, Brian Koss. Proteomic interrogation of the metabolic control of MHC class I antigen presentation in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1892.