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

紫杉醇 癌症研究 巨噬细胞 癌症 重编程 TLR4型 医学 免疫疗法 免疫系统 药理学 生物 细胞 免疫学 体外 内科学 生物化学 遗传学
作者
Carlos W. Wanderley,David F. Colón,João Paulo Mesquita Luiz,Francisco Fábio Bezerra de Oliveira,Paula Ramos Viacava,Caio A. Leite,Janaina A. Pereira,Camila M. Silva,Cássia Regina Silva,Rangel L. Silva,Cesar A. Speck‐Hernandez,José Maurício Mota,José C. Alves‐Filho,Roberto C. Lima-Junior,Thiago M. Cunha,Fernando Q. Cunha
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:78 (20): 5891-5900 被引量:328
标识
DOI:10.1158/0008-5472.can-17-3480
摘要

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. In vitro, 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+/−/TLR4fl/fl), 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. Significance: 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. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5891/F1.large.jpg. Cancer Res; 78(20); 5891–900. ©2018 AACR. See related commentary by Garassino et al., p. 5729
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