Cancer diagnosis & prognosis · 2026
CDKN2A mRNA Over-expression Is Associated With CD8+ T Cell Exclusion and IDO1-Mediated Adaptive Immune Resistance in Gastric Adenocarcinoma.
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Lehrer Steven, Rheinstein Peter
Аннотация
BACKGROUND/AIM: Cellular senescence, mediated by CDKN2A-encoded p16INK4a, generates a senescence-associated secretory phenotype (SASP) that may promote immune evasion in solid tumors. Recent immunohistochemical studies have identified associations between p16INK4a over-expression and CD8+ T cell exclusion in gastric adenocarcinoma, but transcriptomic validation and mechanistic characterization remain limited.
MATERIALS AND METHODS: We analyzed 386 gastric adenocarcinoma samples from The Cancer Genome Atlas (TCGA-STAD) cohort, stratifying patients by CDKN2A mRNA expression using z-score thresholds: Loss (z <-1.0; n=57), Wild-Type (-1.0 ≤ z ≤ +1.0; n=253), and Over-expression (z >+1.0; n=76). Immune cell infiltration was estimated with quanTIseq deconvolution. SASP factor expression (IDO1, TGFB1, NT5E) and correlations with immune populations were assessed using Kruskal-Wallis tests, pairwise Wilcoxon rank-sum tests, and Spearman correlation analyses.
RESULTS: CDKN2A over-expression was significantly associated with CD8+ T cell depletion (p=0.024) and IDO1 up-regulation (p=0.015) compared to wild-type tumors, validating prior immunohistochemical findings. However, TGFB1 (p=0.56) and NT5E (p=0.75) showed no significant differential expression. Paradoxically, IDO1 correlated positively with CD8+ T cell infiltration, as did TGFB1, suggesting reactive up-regulation rather than primary exclusion. Overall survival did not differ significantly across expression groups (p=0.3), nor did stratification by chromosomal instability (CIN p=0.76) or microsatellite instability (MSI p=0.73) molecular subtypes reveal prognostic associations.
CONCLUSION: This transcriptomic analysis confirms the association between CDKN2A over-expression and an immunosuppressive microenvironment characterized by CD8+ T cell depletion and IDO1 up-regulation. The strong positive correlation between IDO1 and CD8+ T cells supports an adaptive immune resistance model, wherein IDO1 is induced via interferon-gamma signaling as a reactive checkpoint rather than functioning as a primary T cell exclusion factor. These findings suggest that CDKN2A-over-expressing gastric adenocarcinomas may benefit from combination immunotherapy strategies incorporating IDO1 inhibition.
MATERIALS AND METHODS: We analyzed 386 gastric adenocarcinoma samples from The Cancer Genome Atlas (TCGA-STAD) cohort, stratifying patients by CDKN2A mRNA expression using z-score thresholds: Loss (z <-1.0; n=57), Wild-Type (-1.0 ≤ z ≤ +1.0; n=253), and Over-expression (z >+1.0; n=76). Immune cell infiltration was estimated with quanTIseq deconvolution. SASP factor expression (IDO1, TGFB1, NT5E) and correlations with immune populations were assessed using Kruskal-Wallis tests, pairwise Wilcoxon rank-sum tests, and Spearman correlation analyses.
RESULTS: CDKN2A over-expression was significantly associated with CD8+ T cell depletion (p=0.024) and IDO1 up-regulation (p=0.015) compared to wild-type tumors, validating prior immunohistochemical findings. However, TGFB1 (p=0.56) and NT5E (p=0.75) showed no significant differential expression. Paradoxically, IDO1 correlated positively with CD8+ T cell infiltration, as did TGFB1, suggesting reactive up-regulation rather than primary exclusion. Overall survival did not differ significantly across expression groups (p=0.3), nor did stratification by chromosomal instability (CIN p=0.76) or microsatellite instability (MSI p=0.73) molecular subtypes reveal prognostic associations.
CONCLUSION: This transcriptomic analysis confirms the association between CDKN2A over-expression and an immunosuppressive microenvironment characterized by CD8+ T cell depletion and IDO1 up-regulation. The strong positive correlation between IDO1 and CD8+ T cells supports an adaptive immune resistance model, wherein IDO1 is induced via interferon-gamma signaling as a reactive checkpoint rather than functioning as a primary T cell exclusion factor. These findings suggest that CDKN2A-over-expressing gastric adenocarcinomas may benefit from combination immunotherapy strategies incorporating IDO1 inhibition.