Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1- profile in a TLR4-dependent manner

Paclitaxel (PCX) is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of PCX is based on microtubule stabilization inducing cell cycle arrest. Here, we use several tumor models to show that PCX not only induces tumor cell cycle arrest, but also promotes antitumor immunity. In vitro, PCX reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. PCX also modulated the tumor-associated macrophages (TAMs) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that PCX altered the M2-like signature of TAMs toward an M1-like profile. In mice selectively lacking TLR4 on myeloid cells e.g. macrophages (LysM-Cre+/-/TLR4fl/fl), the antitumor effect of PCX was attenuated. Gene expression analysis of tumor samples from patients with ovarian cancer before and after treatment with PCX detected an enrichment of genes linked to the M1 macrophage activation profile (IFNy-stimulated macrophages). These findings indicate that PCX skews TAMs towards an immunocompetent profile via TLR4, which might contribute to the antitumor effect of PCX and provide a rationale for new combination regimens comprising PCX and immunotherapies as an anticancer treatment.

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