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]
日期:2018-08-13
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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