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

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Wanderley, Carlos W. ^{[1, 2]} ; Colon, David F. ^[2] ; Luiz, Joao Paulo M. ^[2] ; Oliveira, Francisco F. ^{[1, 2]} ; Viacava, Paula R. ^[2] ; Leite, Caio A. ^[2] ; Pereira, Janaina A. ^[2] ; Silva, Camila M. ^{[1, 2]} ; Silva, Cassia R. ^{[2, 3]} ; Silva, Rangel L. ^[2] ; Speck-Hernandez, Cesar A. ^[2] ; Mota, Jose M. ^[4] ; Alves-Filho, Jose C. ^[2] ; Lima-Junior, Roberto C. ^[1] ; Cunha, Thiago M. ^[2] ; Cunha, Fernando Q. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Fed Ceara, Fac Med, Dept Physiol & Pharmacol, Fortaleza, Ceara - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, CRID, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Fed Uberlandia, Biotechnol Inst, Uberlandia, MG - Brazil

^[4] Univ Sao Paulo, Sao Paulo State Canc Inst, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Cancer Research; v. 78, n. 20, p. 5891-5900, OCT 15 2018.
• Citações Web of Science: 18

Resumo

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(+/-)/TLR4(fl/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 (IFN gamma-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 . (C) 2018 AACR. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs