Prognostic Impact of PD-1 and Tim-3 Expression in Tumor Tissue in Stage I-III Colorectal Cancer

Background: Programmed cell death receptor 1 (PD-1) and T cell immunoglobulin mucin-3 (Tim-3) are considered as important immunosuppressive molecules and play an important role in tumor immune escape and cancer progression. However, it remains unclear whether PD-1 and Tim-3 are coexpressed in stage I-III colorectal cancer (CRC) and how they impact on the prognosis of the disease.

Materials and methods: A total of two cohorts with 451 patients who underwent surgery for stage I-III CRC treatment were enrolled in the study. Among which, 378 cases were from The Cancer Genome Atlas (TCGA) database and 73 cases were from the Fourth Hospital of Hebei Medical University (FHHMU) cohort. The mRNA expressions of PD-1 and Tim-3 in tumor tissue in stage I-III CRC were obtained from TCGA database. Immunohistochemistry was used to assess the expressions of PD-1 and Tim-3 in tumor tissue in stage I-III CRC in the FHHMU cohort. Interactive relationships between PD-1 and Tim-3 were retrieved through the online STRING database, which was used to study the interactions between proteins. DAVID, consisting of comprehensive biological function annotation information, was applied for the GO and KEGG pathway enrichment analysis of the interactive genes.

Results: In the FHHMU cohort, the high expressions of PD-1 and Tim-3 were, respectively, found in 42.47% and 84.93% of stage I-III CRC tissue. PD-1 was significantly associated with age, primary site, and lymphatic metastasis. Tim-3 was closely related to the primary site. Correlation analysis showed that PD-1 and Tim-3 were positively correlated (r = 0.5682, P < 0.001). In TCGA cohort, PD-1 and Tim-3 were associated with the prognosis of CRC patients in terms of 5-year survival (P < 0.05). In the FHHMU cohort, the 5-year survival of patients with high levels of PD-1 and Tim-3 was 54.84% and 65.85%, respectively. Among which, the high expression of PD-1 was associated with poor prognosis (5-year OS: 54.84% vs. 88.10%, P = 0.003). The 5-year survival rate of CRC patients with coexpression of PD-1 and Tim-3 was 45.00%, which was significantly worse than non-coexpression (72.73%, 85.71%, and 90.48% separately). The functional network of PD-1 and Tim-3 primarily participates in the regulation of immune cell activation and proliferation, immune cell receptor complex, cell adhesion molecules, and T cell receptor signaling pathway.

Conclusion: In summary, upregulation of PD-1 and Tim-3 in stage I-III CRC tumor tissue could be associated with the poor prognosis of patients. Those patients with coexpression of PD-1 and Tim-3 may have a significantly worse prognosis.