Within tumors, tumor-associated macrophages (TAMs) usually adopt an M2 phenotype with tumor-promoting characteristics, as opposed to the M1 phenotype responsible for host protection. As acidic pH can affect the characteristics of immune cells, we aimed to test whether low pH as a common stress factor in the tumor microenvironment could be partially responsible for the phenotypic characteristics and/or functional activity of macrophages in prostate cancer. To test this hypothesis, we allowed TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice to develop neoplastic lesions of variable histologic severity. Thereafter, we isolated tumor-associated macrophages from control tumors and analyzed their expression of the M1 and M2 markers; iNos, Il-6, Cd206 and Arg1. Gene expression analysis confirms previous studies which reported higher expression of both M1 and M2 markers in TAMs compared with peritoneal macrophages. Treatment of TRAMP mice with sodium bicarbonate to continuously buffer acids secreted by neoplastic cells, decreased TAMs infiltration into the stromal compartment of prostate. In addition, sodium bicarbonate decreased iNos, Arg1, and Cd206 but not Il-6 expression in TAMs isolated from subcutaneously growing TRAMP-C2 tumors, a TRAMP-derived prostate tumor cell line injected into syngeneic male hosts. Since decreased expression of Arg1 and iNos has been shown to mediate the suppressive activity of myeloid cells, tumor acidity might promote the suppressive microenvironment by upregulating both enzymes. In conclusion, extracellular acidosis increases the density of macrophages and their L-arginine metabolic potential; coincident with delayed tumor progression in prostate tumors.

Citation Format: Asmaa El-Kenawi, Arig Ibrahim-Hashim, Kimberly Luddy, Brian Ruffell, Shari Pilon-Thomas, Robert Gatenby, Robert Gillies. Tumor-secreted acids alter macrophage phenotype. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5101.