A Phosphatidylinositol 3-Kinase Gamma Inhibitor Enhances Anti-Programmed Death-1/Programmed Death Ligand-1 Antitumor Effects by Remodeling the Tumor Immune Microenvironment of Ovarian Cancer

Abstract

Previous studies have shown that the effectiveness of immune checkpoint blockade in the treatment of ovarian cancer (OC) is poor. A promising small molecule inhibitor targeting phosphatidylinositol 3-kinase gamma (PI3Kγ) has recently been applied in combination with other drugs for tumor treatment. This study aimed to determine whether a PI3Kγ inhibitor can enhance the antitumor effects of anti-programmed death-1/programmed death ligand-1 (anti-PD-1/PD-L1) therapies in OC and to explore the underlying immunomolecular mechanism involved. Changes in the expression of PI3Kγ, PD-1, PD-L1, and tumor-associated macrophages (TAMs) during the progression of OC were detected in clinical tissue samples. We also constructed a coculture system of OC cells with lymphocytes for in vitro study, and a subcutaneous and intraperitoneal implantation OC mouse model was constructed for in vivo studies. OC is an immunosuppressed tumor with predominant infiltration of M2 throughout the entire disease course. We also found that a PI3Kγ inhibitor combined with anti-PD-1 therapy can enhance the antitumor effects of anti-PD-1 agents by modulating the PI3Kγ-AKT-NF-κB pathway, reprogramming TAMs, decreasing the number of myeloid-derived suppressor cells, increasing the number of CD8⁺ T cells, and increasing the levels of proinflammatory factors; consequently, this approach transforms the tumor immune microenvironment of OC into a more active state.

Keywords

anti-programmed cell death protein 1/programmed death ligand 1 / ovarian cancer / phosphatidylinositol 3-kinase gamma inhibitor / tumor-associated macrophages / tumor immune microenvironment

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