(3R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one enhanced the therapeutic efficacy of anti-PD1 antibody through inhibiting PI3Kδ/γ.

Purpose: Immunotherapy has demonstrated durable clinical responses in various cancers by disinhibiting the immune system, largely attributed to the success of immune-checkpoint blockade. However, there are still subsets of patients across multiple cancers not showing robust responses to these agents and one significant barrier to their efficacy may be the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. In this study, we demonstrated that functional inhibition of MDSCs with (3 R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIMO), a potent PI3Kδ/γ inhibitor, enhanced the therapeutic efficacy of anti-PD1 antibody in the tumor model. Materials and methods: A syngeneic ovarian tumor model was established. MDSCs from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. Proliferation and killing effects of T-lymphocytes were measured. IFNγ production was measured by ELISA assay. qPCR and western blot were used to detect the gene and protein expression. Furthermore, the therapeutic effects of TIMO combined with anti-PD1 antibody were assessed by the tumor model. Results: Our data demonstrated that inhibition of granulocytic myeloid-derived suppressor cells (G-MDSCs) function with TIMO could overcome MDSCs-mediated immunosuppression and promote antigen-specific T-lymphocyte responses, resulting in the restoration of cytotoxic T cell-mediated tumor control. We further demonstrated that TIMO and anti-PD1 combination therapy promoted tumor growth control in a syngeneic ovarian tumor model. Conclusions: Our results provided proof of concept for a new combination strategy involving the use of a selective inhibitor of PI3Kδ/γ to inhibit the function of MDSCs to enhance tumor responses to immune checkpoint blocking antibodies.