A Comprehensive Study on the Prognostic Value and Clinicopathological Significance of Different Immune Checkpoints in Patients With Colorectal Cancer: A Systematic Review and Meta-Analysis

Abstract

Background: The prognostic significance of immune checkpoint expression in the tumor microenvironment has been widely investigated in colorectal cancers. However, the results of these studies are inconsistent and limited to some immune checkpoints. Objective: The study aimed to investigate the correlation between different immune checkpoint expression and clinicopathological features and prognostic parameters. Methods: We conducted a systematic review and meta-analysis of the published literature in PubMed, Web of Science-Core Collection, Scopus, Embase, and Cochrane databases to summarize the association between various immune checkpoints expression on both tumor cells and immune cells with clinicopathological features and prognostic parameters in patients with colorectal cancer. Results: One hundred four studies incorporating 22,939 patients were included in our meta-analysis. Our results showed that among the B7 family, the high expression of B7H3, B7H4, PD-1, and PD-L1 on tumor cells and tumor tissue was significantly associated with higher T stage, advanced tumor, node, metastasis (TNM) stage, presence of vascular invasion, and lymphatic invasion. In addition, patients with high expression of B7H3, B7H4, PD-1, PD-L1, and PD-L2 were associated with shorter overall survival. High expression of PD-1 and PD-L1 in immune cells correlated with the absence of lymph node metastasis, lower TNM stage, early T stage, poor overall survival, and disease-free survival, respectively. Moreover, we found significant positive correlations between CD70 and Galectin-3 expression with advanced T stage. HLA-II overexpression was correlated with the absence of lymph node metastasis (odds ratio = 0.21, 95 CI = 0.11-0.38, P < 0.001) and early TNM stage (odds ratio = 0.35, 95 CI = 0.26-0.47, P < 0.001). Conclusions: Overexpression of B7H3, B7H4, PD-1, PD-L1, PD-L2, CD70, and Galectin-3 on tumors is significantly associated with unfavorable clinicopathological characteristics and poor prognostic factors. Hence, these immune checkpoints can serve as predictive biomarkers for prognosis and the clinicopathological features of colorectal cancer because this is essential to identify patients suitable for anticancer therapy with immune checkpoint inhibitors.