Abstract 1388: Mutations in transcriptional activators of MHC I antigen presentation, NLRC5 and CIITA, are mutually exclusive and have different effects on melanoma gene transcripts

Abstract

Abstract Response to many immunotherapies depends on effective recognition and eradication of tumor cells by the immune system. This is mediated by the successful presentation of tumor-specific antigens on major histocompatibility complex class I (MHC I) molecules on the surface of tumor cells. Studies have focused on alterations in MHC I complex proteins (e.g. HLA, B2M) and gene regulatory elements (e.g. NLRC5). However, the impact on tumor response of individual defects in components regulating and composing the MHC I antigen processing and presentation machinery (APM) have not been extensively studied. Using a harmonized dataset of six clinical trials of patients with melanoma treated with ICB, whole-exome sequencing (WES, n= 244) and RNA sequencing (RNAseq, n= 426) data from untreated tumor samples were assessed to identify mutations in genes associated with MHC I APM and their regulation. Somatic alterations were correlated with clinical response to ICB and with gene expression profiles in tumor-matched RNAseq data. Mutations in MHC I and MHC I-related genes were found in 63% of patients (n= 154/244). The most recurrently mutated genes were NCAM1 (11%, n=28), TRIM48 (7%, n=17), and CAMK2B (6.6%, n=16), and the transcriptional regulators NLRC5 (9.4%, n=23) and CIITA (9.4%, n=23). Mutations in NLRC5 and CIITA trended toward being mutually exclusive from one another (Fisher’s exact test, p= 0.157) and mutations were overrepresented in tumors with stable or progressive disease following ICB therapy. In addition, lower expression of NLRC5 and CIITA were associated with stable or progressive disease status. NLRC5-mutant tumors that progressed following ICB therapy trended towards lower expression of transcriptional target HLA-A (Kruskal-Wallis, p=0.27); however, there was no difference in HLA-A expression across NLRC5-wildtype tumors. For class II transactivating factor, CIITA, which can induce MHC I expression, mutational status was not associated with HLA-A expression across all clinical response groups. There are genetic alterations spanning MHC I and MHCI-associated genes that may be responsible for inactivating class I antigen presentation by melanoma cells. The impact of these alterations may result in varied clinical responses to ICB therapies. The landscape of these alterations needs to be further delineated to understand how tumors are directly evading class I-mediated recognition and elimination. Citation Format: Mildred Galvez, Katie M. Campbell, Egmidio Medina, Antoni Ribas. Mutations in transcriptional activators of MHC I antigen presentation, NLRC5 and CIITA, are mutually exclusive and have different effects on melanoma gene transcripts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1388.