Physical activity enhances the effect of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACM1 axis.

Abstract

Immune checkpoint blockade therapy has demonstrated significant therapeutic effects in certain types of cancers. However, there is limited reporting on the influence of physical activity on its efficacy. This study aimed to investigate the impact of physical activity on anti-PDL-1-mediated immune checkpoint therapy and the interplay of immune cells therein. HePa1-6 tumor-bearing mice were treated with anti-PDL-1 in conjunction with physical activity to assess tumor progression. Flow cytometry was utilized to analyze immune cell infiltration and differentiation levels within the tumor. The expression of HIF-a/CEACAM1 within the tumor due to physical activity was evaluated. HePa1-6 cells with high CEACAM1 expression were validated in mice to determine their inhibitory effects on immune cell proliferation and differentiation. A CD3/CEACAM1 chimeric antibody was developed for treating CEACAM1-overexpressing tumors, and flow cytometry was employed to assess T-cell response. Physical activity enhanced the efficacy of anti-PDL1 by suppressing the HIF-a/CEACAM1 axis within the tumor. In vivo experiments revealed that tumors with high CEACAM1 expression decreased infiltration and activation of CD8 + T cells within the tumor, suppressing T cell cytotoxicity without affecting Treg infiltration. In vitro, high CEACAM1 expression impacted the proliferation and activation of CD8 + T cells in a co-culture system. The constructed CD3/CEACAM1 chimeric antibody significantly activated the TCR within CEACAM1-overexpressing tumors and inhibited tumor progression. The findings suggest that physical activity augments the effectiveness of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACM1 axis.