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Updated: Dec 21, 2025
Enrichment and Characterization of the Tumor Immune and Non-immune Microenvironments in Established Subcutaneous Murine Tumors
Published on: June 7, 2018
Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal
S Derks1, L K de Klerk2, X Xu3
1Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
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 = 453 GEAs) and archival GEA resection specimen (N = 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 EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+ T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8+ 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.
Insights
Gastroesophageal adenocarcinoma (GEA) subtypes show diverse immune cell profiles. Genome-stable GEAs with tertiary lymphoid structures are promising for immunotherapy, while chromosomal-instable GEAs often evade T cells.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers with variable responses to immune checkpoint inhibitors.
- Microsatellite instability (MSI) and Epstein-Barr virus (EBV)-positive GEAs respond well, unlike diffuse/genome-stable (GS) and chromosomal-instable (CIN) subtypes.
- The tumor microenvironment of CIN and GS GEAs remains undercharacterized, hindering immunotherapy development.
Purpose of the Study:
- To characterize the tumor-immune cell associations across different GEA subtypes.
- To identify potential therapeutic targets for improving immunotherapy in GEA.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) RNAseq data (N=453 GEAs) for computational immune cell subset inference.
- Spatial immune characterization using immunohistochemistry and mRNA expression analyses on archival GEA resection specimens (N=71).
- Correlation of immune cell subsets with tumor characteristics within and between GEA subtypes.
Main Results:
- Substantial heterogeneity in tumor microenvironments across GEA subtypes was confirmed.
- MSI-high and EBV+ GEAs exhibited intense T cell infiltrates.
- GS GEAs showed enrichment of CD4+ T cells, macrophages, and B cells, with tertiary lymphoid structures in ~50% of cases.
- CIN GEAs displayed CD8+ T cells at the invasive margin and tumor-infiltrating macrophages.
- Immunologically 'cold' CIN GEAs were associated with MYC activity and CCNE1 amplification.
Conclusions:
- GEA exhibits diverse immune phenotypes, with GS subtypes showing potential for immunotherapy due to tertiary lymphoid structures.
- CIN GEAs often demonstrate T cell exclusion and infiltrating macrophages, suggesting mechanisms of immune evasion.
- MYC activity and CCNE1 amplification in immune-poor CIN GEAs warrant further investigation for novel therapeutic strategies.
