Paclitaxel Reduces Tumor Growth by Reprogramming Tumor-Associated Macrophages to an M1 Profile in a TLR4-Dependent Manner
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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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Paclitaxel promoted tumor-associated macrophage (TAM) repolarization from M2-like to M1-like phenotype.
“Moreover, paclitaxel promoted tumor-associated macrophage (TAM) to repolarize from M2-like to M1-like phenotype [41].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [41]
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- Authors
- Wanderley, C. W., Colón, D. F., Luiz, J. P. M., Oliveira, F. F., Viacava, P. R., Leite, C. A., Pereira, J. A., Silva, C. M., Silva, C. R., Silva, R. L., Speck-Hernandez, C. A., Mota, J. M., Alves-Filho, J. C., Lima-Junior, R. C., Cunha, T. M., & Cunha, F. Q.
- Affiliations
- Universidade de São Paulo (BR)
- 1Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
- Universidade Federal do Ceará (BR)
- ORCID
- Venue
- Cancer Research
- Published
- 2018-10-15
- Volume
- 78
- Issue
- 20
- Pages
- 5891-5900
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2887408433
- Cited by
- 420
- References
- 52
- Citations by year
- 2026: 26 · 2025: 46 · 2024: 61 · 2023: 52 · 2022: 79 · 2021: 75 · 2020: 50 · 2019: 27 · 2018: 3
- FWCI
- 16.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (2013/08216-2)
- MCTI | Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- paclitaxel, tumor-associated macrophages, M1 macrophage polarization, M2 macrophage reprogramming, TLR4, antitumor immunity, breast cancer, melanoma, ovarian cancer, interferon-gamma, LPS, microtubule stabilization, combination immunotherapy
- MeSH terms
- Animals, Antineoplastic Agents, Breast Neoplasms, Female, Humans, Immune System, Immunotherapy, Macrophage Activation, Macrophages, Melanoma, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Ovarian Neoplasms, Skin Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, NF-kappa B, Paclitaxel, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Cell Line, Tumor, Toll-Like Receptor 4, Mice
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