Paclitaxel Reduces Tumor Growth by Reprogramming Tumor-Associated Macrophages to an M1 Profile in a TLR4-Dependent Manner
| Autor: | Roberto C. P. Lima-Júnior, Thiago M. Cunha, Caio Abner Leite, Francisco Fábio Bezerra de Oliveira, José C. Alves-Filho, Fernando Q. Cunha, Camila A. M. Silva, Janaina A. Pereira, Carlos W. S. Wanderley, Jose Mauricio Mota, João Paulo Mesquita Luiz, Paula Ramos Viacava, David F. Colón, Cássia Regina Silva, Rangel L. Silva, Cesar A. Speck-Hernandez |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MACRÓFAGOS Cancer Research Skin Neoplasms Paclitaxel medicine.medical_treatment Antineoplastic Agents Breast Neoplasms 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Immune system Cell Line Tumor Neoplasms medicine Macrophage Animals Humans Melanoma Oligonucleotide Array Sequence Analysis Ovarian Neoplasms Mice Inbred BALB C Gene Expression Profiling Macrophages NF-kappa B Cancer Immunotherapy Macrophage Activation medicine.disease Gene Expression Regulation Neoplastic Mice Inbred C57BL Toll-Like Receptor 4 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Immune System TLR4 Cancer research Female Ovarian cancer Signal Transduction |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1538-7445 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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