Paclitaxel Reduces Tumor Growth by Reprogramming Tumor-Associated Macrophages to an M1 Profile in a TLR4-Dependent Manner

Abstract

Paclitaxel is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of paclitaxel is based on microtubule stabilization inducing cell-cycle arrest. Here, we use several tumor models to show that paclitaxel not only induces tumor cell-cycle arrest, but also promotes antitumor immunity. , paclitaxel reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. Paclitaxel also modulated the tumor-associated macrophage (TAM) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that paclitaxel altered the M2-like signature of TAMs toward an M1-like profile. In mice selectively lacking TLR4 on myeloid cells, for example, macrophages (LysM-Cre/TLR4), the antitumor effect of paclitaxel was attenuated. Gene expression analysis of tumor samples from patients with ovarian cancer before and after treatment with paclitaxel detected an enrichment of genes linked to the M1 macrophage activation profile (IFNγ-stimulated macrophages). These findings indicate that paclitaxel skews TAMs toward an immunocompetent profile via TLR4, which might contribute to the antitumor effect of paclitaxel and provide a rationale for new combination regimens comprising paclitaxel and immunotherapies as an anticancer treatment. This study provides new evidence that the antitumor effect of paclitaxel occurs in part via reactivation of the immune response against cancer, guiding tumor-associated macrophages toward the M1-like antitumor phenotype. http://cancerres.aacrjournals.org/content/canres/78/20/5891/F1.large.jpg .

Diffuse optical spectroscopic imaging reveals distinct early breast tumor hemodynamic responses to metronomic and maximum tolerated dose regimens

“…Subjects that experienced flare had a relatively small change in deoxyhemoglobin leading to an increase in total hemoglobin and oxygen saturation (Additional file 3: Figure S2), indicating an increase in oxygen supply. This would be consistent with the increased perfusion known to co-occur with an inflammatory response to cytotoxic cellular damage [5,20,25,32,38,51]. The lack of oxyhemoglobin flare in MTD NR patients may indicate poor chemo-and/or immuno-responsiveness, leading to minimal shrinkage of the tumor and potentially poorer outcomes [13,23].…”

Membrane-bound TNF mediates microtubule-targeting chemotherapeutics-induced cancer cytolysis via juxtacrine inter-cancer-cell death signaling

“…It has been known for more than 20 years that high doses of Taxol promotes the secretion of solTNF from macrophages, which occur independently of its microtubulebinding effects [62][63][64][65]. Specifically, the dose for PTX to stimulate macrophage activation (e.g., 10, 30, and 100 μM as reported) was much higher than we reported here (≤1 μM).…”

Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

“…Low-dose paclitaxel changed macrophage phenotype from M2 to M1 through the toll-like receptor (TLR)-4, resulting in tumor growth inhibition [35,36]. This theory is consistent with taxan-containing therapies showing superior results than other regimens for treating gastric cancer [37,38].…”