A mixed phenotype of tumor-associated macrophages and neutrophils is evident within hours of murine mammary carcinoma delivery

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Abstract Most of what we know about tumor associated macrophages (TAM) and tumor associated neutrophils (TAN) comes from analysis of these cells isolated from solid tumors, or the periphery of humans or mice with solid tumors. These studies have largely led to a model in which tumor progression over time creates an environment that leads to the generation of pro-tumor TAM and TAN. If this model is correct then one may expect TAM and TAN that arrive early at tumor sites to largely exhibit an anti-tumor phenotype. In order to address this hypothesis we used a gelatin sponge model to capture TAM and TAN well before a solid tumor was palpable. Not surprisingly, the immune response during the first 72 hours was predominated by Ly6G+ and F4/80+ cells. While TNF-a was the most predominant cytokine produced by these cells, TGF-b was also produced at appreciable levels, and TAM found at the site of the most immunogenic of the tumors exhibited a significant increase in anti-tumor (TNF-a) as well as immune suppressive (arginase, TGF-b) cytokines between 24 to 72 hours post tumor injection. In addition, while there were more ROS+ TAN at the tumor sites compared to control sites at 72 hours, the amount of ROS in the cells at the tumor sites was lower than the amount of ROS in the cells at the control sites. Finally, we looked at metabolism because increased oxidative phosphorylation has been correlated with an immune suppressive phenotype. We found that 72 hours after tumor delivery there was already a significant shift toward oxidative phosphorylation in the TAM. Collectively, these data support the contention that an immune suppressive environment is well underway at the early stages of tumor growth; before a tumor is even palpable.