TAMs, a unique and distinct M2-skewed myeloid population of
tumor stroma, exhibiting pro-
tumor functions is fast emerging as a potential target for anti-
cancer immunotherapy. Macrophage-recruitment and M2-polarization represent key TAMs-related phenomenon that are amenable to therapeutic intervention. However successful translation of these approaches into effective therapeutic regimen requires better characterization of tumor-microenvironment derived signals that regulate macrophage recruitment and their polarization. Owing to hypoxic milieu being a persistent feature of tumor-microenvironment and a major contributor to
malignancy and treatment resistance, the current study was planned with an aim to decipher
tumor cell responses to
hypoxia vis-a-vis macrophage homing and phenotype switching. Here, we show that
hypoxia-primed
cancer cells chemoattract and polarize macrophages to pro-angiogenic M2-polarized subtype via Eotaxin and
Oncostatin M. Concordantly, hypoxic regions of human
breast-cancer specimen exhibited elevated Eotaxin and
Oncostatin M levels with concurrently elevated M2-macrophage content. Blockade of Eotaxin/
Oncostatin M not only prevented hypoxic
breast-cancer cells from recruiting and polarizing macrophages towards an M2-polarized phenotype and retarded
tumor progression in 4T1/BALB/c-syngenic-mice-model of
breast-cancer but also enhanced the efficacy of anti-angiogenic
Bevacizumab. The findings established these two
cytokines as novel targets for devising effective anticancer
therapy particularly for
tumors that are refractory or develop resistance to anti-angiogenic
therapeutics.