Application of immune checkpoint protein for the treatment of cancer

Abstract

Immune checkpoint inhibitor (ICI) induces treatment of cancer clinically. The responses to ICI, however, are only observed in some patients, and the mechanisms explaining the limited response have been studied. To identify the determinants of ICI responses, 160 non-small cell lung cancer patients who had received anti-programmed cell death protein-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) treatment were analyzed. High intracellular adhesion molecule-1 (ICAM-1) levels from plasma or tumors of NSCLC patients results in increased survival. It is observed that soluble ICAM-1 (sICAM-1) in murine syngeneic tumor models improves anti-PD-1 efficacy by cytotoxic T cell activation in further reverse translational studies. In addition, chemokine (CXC motif) ligand 13 (CXCL13) from plasma and tumors has positive correlation with the ICAM-1 level and the efficacy of ICI, indicating that anti-tumor pathway mediated by ICAM-1 might include CXCL13 as an upstream regulator of ICAM-1. Anti-tumor efficacy was enhanced in anti-PD-1-responsive murine tumor models with single treatment of sICAM-1 or co-treatment of sICAM-1 and anti-PD-1. Remarkably, anti-PD-1-resistant tumors are converted to responsive ones in combination of sICAM-1 and anti-PD-1. These results suggest a potential of ICAM-1 as s new immunotherapy for treating cancers.