Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis

Author:

Green Benjamin L.1ORCID,Gamble Lauren A.1ORCID,Diggs Laurence P.1ORCID,Nousome Darryl2ORCID,Patterson Jesse C.3ORCID,Joughin Brian A.3ORCID,Gasmi Billel4ORCID,Lux Stephanie C.1ORCID,Samaranayake Sarah G.1ORCID,Miettinen Markku5ORCID,Quezado Martha5ORCID,Hernandez Jonathan M.1ORCID,Yaffe Michael B.13ORCID,Davis Jeremy L.1ORCID

Affiliation:

1. 1Surgical Oncology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

2. 2Biomedical Informatics and Data Science, Frederick National Laboratory for Cancer Research, NCI, NIH, Frederick, Maryland.

3. 3Koch Institute for Integrative Cancer Research, MIT Center for Precision Cancer Medicine, Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, Maryland.

4. 4Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

5. 5Laboratory of Pathology, NCI, NIH, Bethesda, Maryland.

Abstract

Abstract Stage IA gastric adenocarcinoma, characterized by foci of intramucosal signet ring cells (SRC), is found in nearly all asymptomatic patients with germline pathogenic CDH1 variants and hereditary diffuse gastric cancer syndrome (HDGC). The molecular steps involved in initiating malignant transformation and promoting SRC dormancy in HDGC are unknown. Here, whole-exome bulk RNA sequencing (RNA-seq) of SRCs and adjacent non-SRC epithelium (NEP) was performed on laser-capture microdissected (LCM) regions of interest found in risk-reducing total gastrectomy specimens from patients with HDGC (Clinicaltrials.gov ID: NCT03030404). In total, 20 patients (6 male, 14 female) with confirmed HDGC were identified. Analysis of differentially expressed genes (DEG) demonstrated upregulation of certain individual EMT and proliferation genes. However, no oncogenic pathways were found to be upregulated in SRCs. Rather, SRC regions had significant enrichment in pathways involved in T-cell signaling. CIBERSORTx predicted significant increases in the presence of regulatory T cells (Treg) specific to SRC regions. IHC confirmed an increase in FOXP3+ cells in SRC foci, as well as elevations in CD4+ T cells and HLA-DR staining. In summary, the tumor immune microenvironment is microscopically inseparable from stage IA gastric SRCs using a granular isolation technique. An elevation in CD4+ T cells within SRC regions correlates with clinically observed SRC dormancy, while Treg upregulation represents a potential immune escape mechanism. Implications: Characterization of the tumor–immune microenvironment in HDGC underscores the potential for the immune system to shape the transcriptional profile of the earliest tumors, which suggests immune-directed therapy as a potential cancer interception strategy in diffuse-type gastric cancer.

Funder

National Cancer Institute

National Institutes of Health

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Application of spatial omics in gastric cancer;Pathology - Research and Practice;2024-10

2. Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma;World Journal of Clinical Oncology;2024-09-24

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