TNF Counterbalances the Emergence of M2 Tumor Macrophages

•Tumor-associated macrophages (TAMs) are heterogeneous populations•Loss of type I TNF receptor signaling causes a rise in M2 gene expression in TAMs•TNF mediates a global anti-M2 pathway•TNF suppresses IL-13 production from activated eosinophils

SummaryCancer can involve non-resolving, persistent inflammation where varying numbers of tumor-associated macrophages (TAMs) infiltrate and adopt different activation states between anti-tumor M1 and pro-tumor M2 phenotypes. Here, we resolve a cascade causing differential macrophage phenotypes in the tumor microenvironment. Reduction in TNF mRNA production or loss of type I TNF receptor signaling resulted in a striking pattern of enhanced M2 mRNA expression. M2 gene expression was driven in part by IL-13 from eosinophils co-recruited with inflammatory monocytes, a pathway that was suppressed by TNF. Our data define regulatory nodes within the tumor microenvironment that balance M1 and M2 populations. Our results show macrophage polarization in cancer is dynamic and dependent on the balance between TNF and IL-13, thus providing a strategy for manipulating TAMs.

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