Abstract 4048: Comprehensive analysis of the suppressed tumor immune microenvironment of CIN gastro-esophageal adenocarcinomas

Abstract

Abstract Background and aims: Gastro-esophageal adenocarcinoma (GEA) is a common and lethal disease where immune checkpoint inhibitors have demonstrated efficacy within a minority of patients. Prior studies have identified distinct molecular classes of GEA, characterized by specific features that would be predicted to influence responses to checkpoint therapy. We here perform a comprehensive analysis of tumor immune associations in GEAs to further define the tumor immune microenvironment in distinct classes of GEA and to identify additional candidate mediators of immune evasion that may impact response to immunotherapy efficacy. Methods: Tumor immune interactions in GEAs were studied first using computational analyses to infer immune cell subsets from RNAseq data generated from The Cancer Genome Atlas (TCGA). These data were complemented by additional focused studies spanning immunohistochemistry, gene expression profiling and flow cytometry on archival tissue samples and from freshly resected GEA tumor samples. Results: Our results confirmed substantial heterogeneity in the composition of the tumor immune microenvironment between distinct GEA subtypes. As shown earlier, tumors with microsatellite instability (MSI) or Epstein-Barr virus (EBV) harbored larger T cell infiltrates in contrast to those with chromosomal instability (CIN), the most common class of GEA. We then focused greater attention on the CIN cohort, finding a spectrum of phenotypes including tumors with ‘immune hot' and ‘immune cold' states. The ‘hot' cases were more often from Western patients and had greater degrees of DNA methylation. Notably, these tumors often showed co-expression of secondary immune checkpoint proteins, as confirmed by flow cytometry. There was no association between number of infiltrating T cells and mutational or neoantigen load within the CIN GEA subgroup. Immunological cold CIN GEAs were characterized by a higher level of chromosomal instability, enrichment of cell cycle pathways, specifically amplification of cyclin E1, CCNE1, and enrichment of an unfolded protein response. Citation Format: Sarah Derks, Xinsen Xu, Leonie de Klerk, Tania Fleitas, Kevin Liu, Yang Liu, Claire A. Margolis, Felix Dietlein, Anna Maria Chiaravalli, Annacarolina da Silva, Gordon Freeman, Scott J. Rodig, Eliezer M. Van Allen, Bo Li, Jingxin Fu, Jin Wang, Shirley X. Liu, Adam J. Bass. Comprehensive analysis of the suppressed tumor immune microenvironment of CIN gastro-esophageal adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4048.