Abstract 584: Synergistic action of ATF6 and EZH2 in sensing metabolic stress to boost anti-tumor immunity

Abstract Although immune checkpoint blockade (ICB) marked a breakthrough in melanoma treatment, half of patients fail to respond, underscoring the crucial need for complementary adjuvant and neo-adjuvant therapies. Due to the low overall response rate and the stark contrast in outcomes between patients that respond and those that fail to respond, identifying the defining characteristics of immune checkpoint blockade (ICB) response is essential for enhancing the efficacy of melanoma treatments. To recapitulate and investigate the ICB-responsive phenotype in vitro, melanoma cells were metabolically adapted to an environment lacking glucose which successfully drove the dependence on oxidative metabolism and restored MHC-I expression, two established characteristics of ICB responsive tumors. Further, metabolic adaptations significantly enhance the tumor sensitivity to T-cell killing. Surprisingly even in JAK1 and IFNAR1 deficient cells, metabolic adaptation restored MHC I antigen presentation, indicating an interferon-independent mechanism of MHC-I regulation. Proteomic analysis of three metabolically conditioned melanoma cells lines (human and mouse) identified downregulation of the histone methyltransferase EZH2 and the activating transcription factor ATF6 as key corollaries of MHC-I expression. Interestingly, EZH2 and ATF6 activity were found to be inversely related in metabolically adapted cells and patient tumor samples. These studies mechanistically explore the epigenomic control of antigen presentation machinery and the transcriptional targets of ATF6 controlling sensitivity T cell killing. Here, through in vitro and in vivo studies, we demonstrate that constitutive activation of ATF6, and thereby activation of the adaptive unfolded protein response (UPR), sensitizes melanoma to immune control. These data suggest that EZH2 and ATF6 act synergistically to balance immune mediated killing during metabolic stress whereby loss of EZH2 increases MHC-I antigen presentation and activation of ATF6 sensitizes tumor cells to T cell-mediated control. Ongoing therapeutic studies combining EZH2 inhibition, ATF6 activation, and ICB in pre-clinical models further suggest targeting the synergy between EZH2 and ATF6 is a putative adjuvant or neo-adjuvant target to improve the clinical response of ICB. Citation Format: Jacob L. Edmondson, Megan R. Reed, Daniel Fil, Billie Heflin, Brian Koss, Alan J. Tackett. Synergistic action of ATF6 and EZH2 in sensing metabolic stress to boost anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 584.