PMN-MDSC Infiltration Blocks the Antitumor Effects of CSF1R Inhibition

Tumor-associated macrophages (TAM) promote tumor progression by suppressing T-cell function and promoting tumor angiogenesis, proliferation, survival, and metastasis. CSF1/CSF1R signaling is required for TAM differentiation and survival, and thus has emerged as a potential therapeutic target to inhibit TAMs. However, CSF1R inhibitors have not had clinical success as single agents, although preclinical studies have demonstrated antitumor efficacy in combination with radiation therapy and immune checkpoint inhibitors. Kumar and colleagues sought to understand the mechanism by which CSF1R inhibitors affect tumor progression. In mouse models of melanoma, lymphoma, and lung, colon, breast, and prostate cancers, CSF1R inhibition reduced TAMs as expected, but had little effect on tumor progression. CSF1R inhibition also induced accumulation of protumorigenic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), suggesting that the therapeutic effect of suppressing TAMs may be offset by the increase in PMN-MDSCs. Mechanistically, tumor cells secreted CSF1 that induced an HDAC2-mediated downregulation of chemokines (including CXCL1) responsible for recruitment of PMN-MDSCs in carcinoma-associated fibroblasts (CAF). Conversely, CSF1 inhibition upregulated chemokines and the CXCL1 receptor CXCR2 to promote PMN-MDSC recruitment, and this effect was confirmed in patients with cancer. These findings suggested the possibility for combined targeting of CSF1R and CXCR2 to prevent TAM accumulation and PMN-MDSC recruitment. Combined inhibition of CSF1R and CXCR2 decreased TAMs, prevented PMN-MDSC accumulation, and suppressed tumor progression in mouse models of melanoma and lung carcinoma, whereas treatment with either inhibitor alone had little effect on tumor growth. Further, dual inhibition of CSF1R and CXCR2 enhanced the efficacy of immune checkpoint blockade with anti–PD-1. Taken together, these results indicate that the antitumor activity of CSF1R inhibitors may be potentiated by the addition of CXCR2 inhibitors to prevent recruitment of PMN-MDSCs.

Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F, Lavilla-Alonso S, et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 2017;32:654–68.e5.

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