Single-Cell Transcriptional States of Human Leukocyte Antigen DR Positive CD4 Positive T Cells Linked to Genetic Susceptibility of Gastric Cancer.

Authors

Yicun Song, Haoran Zhu, Cong Qiao, Yueying Wang

Published in

Immunological investigations. Pages 1-32. Aug 06, 2026. Epub Aug 06, 2026.

Abstract

Gastric cancer (GC) involves complex immune-metabolic crosstalk, but MR-prioritized immunophenotypes and mediating metabolites remain unclear.
Two-sample Mendelian randomization (MR) was performed using GWAS summary data for 731 immunophenotypes, 1,400 circulating metabolites, and GC (218,792 European participants). Instruments were selected at p < 1 × 10^-5, LD-clumped (r² < 0.001, 10,000 kb), and filtered for strength (F > 10). IVW served as the primary estimator, with sensitivity and reverse MR analyses. Two-step MR explored metabolite-mediated pathways. Single-cell RNA-seq from 56 samples across three sources was integrated to resolve HLA-DR⁺ CD4⁺ T-cell transcriptional states, evaluate GC genetic-risk enrichment via scDRS, and infer cell-cell communication using CellChat.
Twenty-six immunophenotypes showed candidate associations with GC. HLA-DR expression on HLA-DR⁺ CD4⁺ T cells was inversely associated with GC risk (OR = 0.761, 95% CI 0.634-0.912, FDR q = 0.0393). Reverse MR was not FDR-significant, and MR-Egger indicated no directional pleiotropy. Candidate mediation involved bilirubin degradation product C17H18N2O4(2). Single-cell analysis identified five HLA-DR⁺ CD4⁺ T-cell subsets; T1 and T5 showed relatively higher GC genetic-susceptibility enrichment, with T5 exhibiting low CytoTRACE scores. These subsets were linked to immune activation and chemokine signaling. The exploratory TIGIT-NECTIN2 signal was not robustly retained after CellChat sensitivity filtering.
This study suggests a potential inverse association between HLA-DR⁺ CD4⁺ T-cell immunophenotypes and GC risk, with bilirubin-related metabolites as a candidate mediating pathway. Subsets T1/T5 provide candidate directions for future GC immune-prevention research.

PMID:
42560142
Bibliographic data and abstract were imported from PubMed on 06 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.