The PI3 kinases (PI3K) belong to a family of signal-transducing enzymes that mediate key cellular functions in cancer and immunity. The PI3K-gamma (γ) isoform plays an important role in macrophage/myeloid cell function and migration, and a role for PI3K-γ in tumor growth and immune tolerance has been established in studies utilizing PI3K-γ knockout (KO) mice (Schmid et al., Cancer Cell, 2011; Gunderson et al., Cancer Discovery, 2015). We propose that pharmacological inhibition of PI3K-γ in myeloid cells can alter the tumor-immune microenvironment leading to enhanced antitumor T-cell responses. IPI-549 is an oral, potent, and selective inhibitor of PI3K-γ. Prior studies showed single agent antitumor activity in multiple murine tumor models, and enhanced antitumor activity and improved survival when combined with immune-checkpoint blockade. This antitumor activity is dependent on the presence of both immune-suppressive tumor-associated CD11b+ myeloid cells and CD8+ cytotoxic T cells. IPI-549 can reduce the T-cell-suppressive activity of both murine and human myeloid-derived suppressor cells in vitro (Kutok et al, 2015 CRI-CIMT-EATI-AACR Cancer Immunotherapy Meeting; De Henau et al, 2016 AACR Annual Meeting). We now show that IPI‑549 treatment of tumor‑bearing mice leads to a shift in tumor-associated myeloid cells from an immunosuppressive M2 phenotype to a proinflammatory M1 phenotype, characterized by reduced CD206 expression and enhanced expression of MHC class II and NOS2. Compared to vehicle-treated controls, short-term (9 days) treatment of CT26 tumor‑bearing animals with IPI‑549 revealed an increased frequency of circulating tumor-specific T cells, an increased percentage of tumor-infiltrating CD8+IFNγ+ T cells, and a reduced percentage of CD4+Foxp3+ regulatory T cells, leading to a trend towards increasing the CD8+/T-reg cell ratio. Treatment of 4T1 and B16GM tumor-bearing mice with IPI-549 for 14 days led to a significant increase in the CD8+/T-reg cell ratio. Together these data show that IPI-549 treatment leads to a proinflammatory tumor microenvironment. Importantly, gene and protein expression analysis of whole tumor tissue collected from IPI-549-treated mice revealed a cytotoxic T-cell signature characterized by increased production of proinflammatory cytokines, and enhanced expression costimulatory and coinhibitory genes relative to vehicle-treated animals. These findings indicate that IPI-549 increases antitumor immunity by remodeling the tumor-immune microenvironment via blockade of tumor-associated myeloid cells. In addition, the up-regulation of costimulatory and coinhibitory genes with IPI-549 treatment provides a mechanistic rationale for the observed combination activity with immune checkpoint inhibition. IPI-549 is currently in Phase I development, both as a single agent and in combination with an anti-PD-1 antibody, in solid tumors (ClinicalTrials.gov NCT02637531).
Citation Format: Matthew Rausch, Jeremy Tchaicha, Thomas Tibbitts, Olivier De Henau, Sujata Sharma, Melissa Pink, Joseph Gladstone, Jennifer Proctor, Mark Douglas, Howard Stern, Taha Merghoub, Jedd Wolchok, Karen McGovern, Jeff Kutok, David Winkler. The PI3K-γ inhibitor, IPI-549, increases antitumor immunity by targeting tumor-associated myeloid cells and remodeling the immune-suppressive tumor microenvironment [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B032.
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