Diet restriction enhances the effect of immune checkpoint block by inhibiting the intratumoral mTORC1/B7‐H3 axis

Abstract

AbstractImmune checkpoint blockade therapy has demonstrated significant therapeutic efficacy in certain cancer types; however, the impact of dietary restriction remains scarcely reported in this context. This study aimed to investigate the influence of dietary restriction on anti‐PDL‐1 therapy and the interplay of immune cells within this context. Using an anti‐PDL‐1 regimen combined with dietary restrictions, tumor progression was assessed in LLC‐bearing mice. Flow cytometry was employed to analyze immune cell infiltration and differentiation levels within the tumor microenvironment. The expression of mTORC1/B7‐H3 in tumors subjected to dietary restriction was also examined. LLC tumors with elevated B7‐H3 expression were validated in mice to determine its inhibitory effect on immune cell proliferation and differentiation. A CD3/B7‐H3 chimeric antibody was developed for therapeutic intervention in B7‐H3 overexpressing tumors, with subsequent T cell responses assessed through flow cytometry. Dietary restriction potentiated the effect of anti‐PDL1 therapy by suppressing the intratumorally mTORC1/B7‐H3 axis. In vivo experiments demonstrated that elevated B7‐H3 expression in tumors reduced infiltration and activation of CD8 + T cells within the tumor, while it did not affect tumor‐infiltrating Tregs. In vitro studies revealed that high B7‐H3 expression influenced the proliferation and activation of CD8 + T cells within a Coculture system. The constructed CD3/B7‐H3 chimeric antibody prominently activated TCR within B7‐H3 overexpressing tumors and impeded tumor progression. The findings suggest that dietary restriction enhances the efficacy of immune checkpoint blockade by modulating the intratumoral mTORC1/B7‐H3 axis.