β-Glucan-conjugated anti-PD-L1 antibody enhances antitumor efficacy in preclinical mouse models

Abstract

The use of immune checkpoint blockade (ICB) is a promising approach for clinical cancer treatment. However, most of cancer patients do not respond to anti-PD-1/PD-L1 antibody. In this study, we proposed a novel strategy of antibody-β-glucan conjugates (AGC) to enhance the antitumor immune response to ICB therapy. The AGC were constructed by conjugating an anti-PD-L1 antibody with a β-glucan via click chemistry. This design facilitates the delivery of β-glucan into the tumor microenvironment (TME). Furthermore, the bridging effect mediated by AGC can promote the interaction between tumor cells and dendritic cells (DCs), thereby enhancing immunotherapeutic benefits. In the MC38 tumor-bearing mouse model, AGC demonstrated powerful tumor suppression, achieving a tumor suppression rate of 86.7 %. Immunophenotyping, cytokine analysis, RNA sequencing, and FTY720-treated models were combined to elucidate the mechanism underlying AGC function. Compared with anti-PD-L1 antibody, AGC induced an earlier immune response, infiltration of DCs, and activation of preexisting T cells in the TME, with T cells predominantly proliferating locally rather than migrating from other organs. In conclusion, these data suggest that AGC could serve as a promising strategy to improve ICB therapy with prospects for clinical utilization.

Keywords: Antibody–β-glucan conjugates; Antitumor; Immune checkpoint inhibitors; Immunotherapy; β-Glucan.