Abstract LB041: EZH2 and ATF6 sense metabolic stress to balance MHC class I antigen presentation in melanoma

• Published in: Cancer research (Chicago, Ill.) Vol. 83; no. 8_Supplement; p. LB041
• Main Authors: Edmondson, Jacob L., Reed, Megan R., Morehead, Lauren C., Heflin, Billie, Koss, Brian, Tackett, Alan J.
• Format: Journal Article
• Language: English
• Published: 14.04.2023
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-LB041

Abstract Unleashing the immune anti-tumor response through immune checkpoint inhibitors (ICIs) is a promising strategy to combat many solid-tumor malignancies, including metastatic melanoma. When successful, the anti-tumor response is potent; however, around half of melanoma patients fail to respond to ICIs. Patient responsiveness to ICIs has been characterized by increases in MHC class I (MHC-I) expression driven by increases in oxidative metabolism. Though the harsh conditions of the tumor microenvironment (TME) are known to be immunosuppressive, the specific mechanisms connecting metabolic stress and antigen presentation are not well understood. To recapitulate and investigate the ICI-responsive phenotype in vitro, a model of metabolic remodeling was developed which forces melanoma cells (A375, A101D, B16F10) to metabolically adapt to the absence of glucose. Proteomic profiling indicates a reversible, adaptive phenotype reminiscent of published ICI-responders, and pathway enrichment shows analogous increases in oxidative metabolism and restoration of MHC-I expression. This phenotype, and its impact on MHC-I expression, significantly increases tumor cell sensitivity to T-cell-mediated killing in vitro. Additionally, successful adaptive remodeling of JAK1 and IFNAR1 KO cell lines suggests the metabolism-mediated induction of MHC-I is independent of IFN signaling. Proteomic analysis of three metabolically conditioned melanoma cell lines identified downregulation of the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) and the activating transcription factor ATF6 as key determinants of MHC expression. In these studies, we mechanistically explore the control of MHC-I antigen presentation through the transcriptional and post-translational dysregulation of ATF6 and EZH2. Here, we demonstrate that ATF6 overexpression, and thereby activation of the adaptive unfolded protein response (UPR), prevents induction of MHC by EZH2 inhibition. These data suggest EZH2 and ATF6 act to balance MHC-I antigen presentation during metabolic stress whereby loss of EZH2 increases and activation of ATF6 prevents MHC antigen presentation. Additional and ongoing studies coupling EZH2 and ATF6 inhibition will provide crucial insight into this mechanism and have the potential to influence adjuvant therapy development. Citation Format: Jacob L. Edmondson, Megan R. Reed, Lauren C. Morehead, Billie Heflin, Brian Koss, Alan J. Tackett. EZH2 and ATF6 sense metabolic stress to balance MHC class I antigen presentation in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB041.