Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas

Abstract

Background: Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers where immune checkpoint inhibitors have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr virus (EBV)-positive subtypes. Immune checkpoint inhibitor responses are markedly lower in diffuse/genome stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies. Patients and methods: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (N ¼ 453 GEAs) and archival GEA resection specimen (N ¼ 71). The Cancer Genome Atlas RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristics within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses. Results: Our results confirmed substantial heterogeneity in the tumor microenvironment between distinct subtypes. While MSI-high and EBVþ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4þ T cells, macrophages and B cells and, in w50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8þ T cells predominantly at the invasive margin while tumor-associated macrophages showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1. Conclusions: These results reveal the diversity of immune phenotypes of GEA. Half of GS gastric cancers have tertiary lymphoid structures and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.

Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability–High Gastric Cancer

“…Whether serial analysis of circulating tumor DNA could guide adaptive strategies to boost response remains to be seen. Beyond tumor genomic changes, there is a clear interplay between TME and tumor clones in GC (39,46,47). Our scRNAseq data supported clear differences in both baseline and adaptive TME composition between responders and non-responders.…”

Exosome-mediated communication between tumor cells and tumor-associated macrophages: implications for tumor microenvironment

“…As a vital plastic and heterogeneous population of cells in the TME, TAMs account for 30%-50% of infiltrating immune cells. 12 Circulating monocytes extravasate from nearby blood vessels and enter tumor tissue, contributing to their polarization into different phenotypes. 13 , 14 …”

Gastric Carcinomas with Stromal B7-H3 Expression Have Lower Intratumoural CD8+ T Cell Density

“…Different histological types may differ in their ability to recruit CD8+ T cells into the TC and IF. Moreover, tumours with higher TIL infiltrates have better adaptive immune response and, thus, they respond to immune checkpoint inhibitors more effectively [ 15 ].…”

“…Derks et al described heterogeneity in TIME among GC molecular subtypes. In their study, chromosomal instable GCs ( n = 18) showed T cell exclusion and possessed CD8+ cells predominantly at the invasive margin [ 15 ]. We noticed a similar pattern in B7-H3-high GCs and, thus, propose that B7-H3 could be involved in this immune suppressive mechanism of TIME.…”