Integrating COX-2, stromal PD-L1, and T-cell infiltration enhances prognostic stratification in colorectal cancer

Colorectal cancer (CRC) is shaped by a complex tumor immune microenvironment in which inflammatory mediators like cyclooxygenase-2 (COX-2) and immune checkpoints such as programmed cell death ligand 1 (PD-L1) play central regulatory roles. However, the prognostic significance of these makers, individually and in combination with T-cell infiltration, remains poorly defined. We investigated the interplay between PD-L1, COX-2, 15-hydroxy prostaglandin dehydrogenase (15-PGDH), and TILs using both an internal immunohistochemistry (IHC)-based CRC cohort (n = 320) and large public transcriptomic datasets (GSE39582, TCGA-COAD, and E-MTAB-12862). Immune cell composition was analyzed using CIBERSORTx and single-sample gene set enrichment analysis (ssGSEA), and tumors were stratified by consensus molecular subtypes (CMS). Prognostic relevance was evaluated through survival modeling and risk signature development. PD-L1 expression in the tumor stroma (TS⁺ PD-L1) demonstrated stronger prognostic value than cancer cell-specific PD-L1 (CC+ PD-L1) and correlated positively with COX-2 expression and TIL abundance. Across all cohorts, CD274, PTGS2, and CD8A expression were strongly correlated and enriched in CMS1 tumors. High PTGS2 tumors exhibited inflamed but often immunosuppressive phenotypes, marked by elevated IFN-γ and inflammatory response pathway scores. Multivariate survival analyses confirmed that the combined expression of TS⁺ PD-L1, COX-2, and TIL markers outperformed single-marker models. A composite IHC-based immune-inflammation risk score improved prognostic prediction over TNM staging alone. PD-L1 and COX-2 define a conserved immunoregulatory axis in CRC that shapes tumor-immune interactions and impacts prognosis. Integration of TS+ PD-L1, inflammatory markers, and T-cell contexture enhances risk stratification and may inform future immunotherapeutic and chemopreventive strategies.