Specific inhibition of PI3Kδ/γ enhances the efficacy of anti-PD1 against osteosarcoma cancer

• Main Authors: Xinge Shi, Xiqing Li, Hongqiang Wang, Zhenghong Yu, Yu Zhu, Yanzheng Gao
• Format: Article
• Language: English
• Published: Elsevier 2019-06-01
• Series: Journal of Bone Oncology
• Online Access: http://www.sciencedirect.com/science/article/pii/S221213741830099X

ABSTRACT: Impressive responses have been observed in patients with cancer treated with checkpoint inhibitory anti-programmed cell death-1 (PD-1) or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies through disinhibiting the immune system. However, tumors possess complex immunosuppressive tumor microenvironment to present therapeutic obstacles and the response rates to immune checkpoint inhibition remain low. One significant barrier to the efficacy of anti-PD1 treatment is the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor. MDSCs dramatically increased in peripheral blood of patients with osteosarcoma and prohibited both T-cell activation and infiltration. Here we demonstrated functional inhibition of G-MDSCs with (S)-(-)-N-[2-(3-Hydroxy-1H-indol-3-yl)-methyl]-acetamide (SNA), a specific inhibitor of PI3Kδ/γ, could prime tumor microenvironment, resultantly enhancing the therapeutic efficacy of anti-PD1 treatment in a syngeneic osteosarcoma tumor model. Combining SNA with anti-PD1 dramatically slowed osteosarcoma tumor growth and prolonged survival time of tumor-bearing mice, at least in part mediated through CD8+ T cells. Our results demonstrated that addition of SNA to anti-PD1 significantly altered infiltration and function of innate immune cells, providing the rationale for combination therapy in patients with osteosarcoma through inhibiting the function of MDSCs with a selective PI3Kδ/γ inhibitor to enhance responses to immune checkpoint blockade. Key words: (S)-(-)-N-[2-(3-Hydroxy-1H-indol-3-yl)-methyl]-acetamide, MDSCs, Osteosarcoma, Anti-PD1