Innate immune cells (macrophages, monocytes and neutrophils) rapidly migrate to sites of tissue damage where they initially activate T cells (M1 classical response). These cells gradually transition to suppress T cell responses, while stimulating wound healing (M2 alternative response). In tumors, however, the normal immune response is chronically disrupted and an exaggerated immunosuppressive, wound healing, tumor-promoting (M2) response prevails. In order to identify the mechanisms regulating this M2 response in tumor inflammation and to develop novel therapeutics to control it, we set out to explore the role of macrophage signaling in control of the M1-M2 switch.

Using RNA seq analysis of gene expression patterns in M1 and M2 macrophages in vitro and gene expression analysis of myeloid cells in spontaneous and orthotopic mouse models of lung, pancreatic and breast cancer, we found that myeloid cell PI3Kinase gamma controls the switch between the M1-M2 phenotype in human and murine macrophages. PI3Kinase gamma signaling stimulates an immunosuppressive, wound healing gene expression program exemplified by expression of immunosuppressive and pro-angiogenic factors, such as Arginase1, TGFbeta1, PDGFBB, MMP9, and MMP13, and suppression of pro-inflammatory factors such as IL12, iNos, and interferon gamma. Blockade of this pathway by genetic or pharmacological inhibition of PI3Kgamma blocks this immunosuppressive, wound healing gene expression program and stimulates instead a T cell activating gene expression program as well as T cell mediated tumor cell killing. PI3Kgamma blockade inhibits tumor growth and metastasis in mouse models of lung, pancreatic and breast carcinoma. Our studies demonstrate the critical role of PI3Kgamma signaling in the control of the M1-M2 macrophage switch and demonstrate that this kinase is an important therapeutic target to suppress tumor growth by targeting inflammation that is associated with all solid tumors.

Citation Format: Megan Kaneda, Sara Gorjestani, Judith A. Varner. PI3-kinase gamma controls the macrophage M1-M2 switch, thereby promoting tumor immunosuppression and progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3650. doi:10.1158/1538-7445.AM2014-3650