S Derks1, L K de Klerk2, X Xu3, T Fleitas4, K X Liu5, Y Liu6, F Dietlein7, C Margolis7, A M Chiaravalli8, A C Da Silva9, S Ogino10, F G Akarca11, G J Freeman11, S J Rodig12, J L Hornick9, E van Allen7, B Li13, S X Liu13, V Thorsson14, A J Bass15. 1. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands. Electronic address: s.derks@amsterdamumc.nl. 2. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands; Dana-Farber Cancer Institute, Boston, USA. 3. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 4. Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain. 5. Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, USA. 6. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, USA. 7. Dana-Farber Cancer Institute, Boston, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, USA. 8. Department of Pathology, Ospedale di Circolo, Varese, Italy. 9. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, USA. 10. Dana-Farber Cancer Institute, Boston, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA. 11. Dana-Farber Cancer Institute, Boston, USA. 12. Department of Pathology and Center for Immuno-Oncology. 13. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA. 14. Institute for Systems Biology, Seattle, USA. 15. Dana-Farber Cancer Institute, Boston, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, USA. Electronic address: adam_bass@dfci.harvard.edu.
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 = 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.
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.
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