Abstract LB-152: Macrophage control of cancer cell stemness and tumor metastasis

Abstract

Abstract A characteristic feature of cancer is the presence of an abundant inflammatory infiltrate, which includes tumor-associated macrophages. In response to diverse tumor-derived chemoattractants, macrophages invade the tumor microenvironment, promoting angiogenesis, growth, immunosuppression and metastasis. Because they stimulate tumor progression and metastasis, it is possible that tumor-associated macrophages enhance cancer initiating cell populations leading to increased tumorigenicity and metastasis. In the tumor microenvironment, macrophages are characterized into having two phenotypes, classical (M1) or alternative (M2). M2 macrophages suppress T-cell activation and promote angiogenesis and tumor progression, while M1 macrophages produce immunostimulatory cytokines and stimulate T cell mediated anti-tumor immunity. Whether and how macrophages affect cancer cell stemness and metastasis is not well understood. Recently our lab showed that suppression of PI3Kinase-gamma signaling in myeloid cells leads to a reduction in tumor growth, angiogenesis, and metastasis. Genetic or pharmaceutical blockade of PI3Kinase-gamma or its target alpha4beta1 integrin inhibits the trafficking of monocytes to tumors and blocks expression of M2 macrophage factors, such as TGF-beta, Arginase and IL-6. To discover how PI3Kinase-gamma regulates the macrophage phenotype we performed RNA sequencing (RNA-seq) of classical and alternative polarization conditions in PI3Kinase-gamma-deficient and WT macrophages. Using this approach, we identified gene clusters associated with tumor immunity and metastasis that are regulated by PI3Kinase-gamma. Furthermore, we observed that macrophages polarized to the M2 phenotype enhanced the colony formation of breast and lung cancer cell lines in an anchorage independent tumor spheroid outgrowth assay whereas M1 polarization inhibited colony formation. Taken together, our data support the hypotheses that PI3Kinase-gamma expressing M2 macrophages promote cancer cell stemness and tumor metastasis. These studies could lead to new approaches for cancer therapy by encouraging the use of PI3Kinase-gamma antagonists as adjuvants for immunotherapy of human cancer. Citation Format: Sara Gorjestani. Macrophage control of cancer cell stemness and tumor metastasis. [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 LB-152. doi:10.1158/1538-7445.AM2014-LB-152