Co-expression of PD-1 with TIGIT or PD-1 with TIM-3 on tumor-infiltrating CD8⁺ T cells showed synergistic effects on improved disease-free survival in treatment-naïve CRC patients

Immune checkpoints (ICs) are highly expressed on tumor-infiltrating immune cells (TIICs) in different malignancies, including colorectal cancer (CRC). T cells play crucial roles in shaping CRC, and their presence in the tumor microenvironment (TME) has proven to be one of the best predictors of clinical outcomes. A crucial component of the immune system is cytotoxic CD8⁺ T cells (CTLs), which play decisive roles in the prognosis of CRC. In this study, we investigated associations of immune checkpoints expressed on tumor-infiltrating CD8⁺ T cells with disease-free survival (DFS) in 45 naïve-treatment CRC patients. First, we examined the associations of single ICs, and found that CRC patients with higher levels of T-cell immunoglobulin and ITIM-domain (TIGIT), T-cell immunoglobulin and mucin domain-3 (TIM-3) and programmed cell death-1 (PD-1) CD8⁺ T cells tended to have longer DFS. Interestingly, when PD-1 expression was combined with other ICs, there were more evident and stronger associations between higher levels of PD-1⁺ with TIGIT⁺ or PD-1⁺ with TIM-3⁺ tumor-infiltrating CD8⁺ T cells and longer DFS. Our findings for TIGIT were validated in The Cancer Genome Atlas (TCGA) CRC dataset. This study is the first to report on the association of co-expression of PD-1 with TIGIT and PD-1 with TIM-3 in CD8⁺ T cells and improved DFS in treatment-naïve CRC patients. This work highlights the significance of immune checkpoint expression on tumor-infiltrating CD8⁺ T cells as critical predictive biomarkers, especially when co-expression of different ICs is considered.