STAT3/NF‐κB signalling disruption in M2 tumour‐associated macrophages is a major target of PLGA nanocarriers/PD‐L1 antibody immunomodulatory therapy in breast cancer

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dc.contributor.authorCavalcante, Rômulo
dc.contributor.authorIshikawa, Uta
dc.contributor.authorSilva, Emanuell
dc.contributor.authorSilva Jr, Arnóbio
dc.contributor.authorAraújo, Aurigena
dc.contributor.authorCruz, Luis
dc.contributor.authorChan, Alan
dc.contributor.authorAraújo Jr, Raimundo
dc.contributor.authorID0000-0001-6418-2454pt_BR
dc.date.accessioned2022-10-07T16:27:38Z
dc.date.available2022-10-07T16:27:38Z
dc.date.issued2021-03-31
dc.description.resumoBackground and Purpose Inflammation associated with the tumour microenvironment (TME) is critical for cancer development, and immunotherapeutic strategies modulating the immune response in cancer have been crucial. In this study, a methotrexate‐loaded (MTX) poly(lactic‐co‐glycolic acid)‐based (PLGA) drug nanocarrier covered with polyethyleneimine (Pei) and hyaluronic acid (HA) was developed and combined with an PD‐L1 antibody to investigate anti‐cancer and immunomodulatory effects in breast cancer TME. Experimental Approach Naked or HA‐coated PeiPLGA‐MTX nanoparticles (NPs) were assessed on 4T1 breast cancer cells grown in culture and in a mouse model of orthotopic tumour growth. Tumours were evaluated by qRT‐PCR and immunohistochemistry. The cell death profile and cell migration were analysed in vitro in 4T1 cells. Polarization of murine macrophages (RAW cells) was also carried out. Key Results Naked or HA‐coated PeiPLGA‐MTX NPs used alone or combined with PD‐L1 antibody modified the tumourigenic course by TME immunomodulation, leading to reduction of primary tumour size and metastases. STAT3 and NF‐κB were the major genes downregulated by NPs. In tumor‐associated macrophages (TAM) such regulation switched M2 phenotype (CD163) towards M1 (CD68) and reduced levels of IL‐10, TGF‐β and CCL22. Moreover, malignant cells showed overexpression of FADD, APAF‐1, caspase‐3 and E‐cadherin, and decreased expression of Bcl‐2, MDR‐1, survivin, vimentin, CXCR4 and PD‐L1 after treatment with NPs. Conclusion and Implications NPs‐mediated STAT3/NF‐κB signalling axis suppression disrupted crosstalk between immune and malignant cells, reducing immunosuppression and critical pro‐tumour events. These findings provide a promising therapeutic approach capable of guiding the immune TME to suppress the development of breast cancer.pt_BR
dc.identifier.citationCavalcante, R. S., Ishikawa, U., Silva, E. S., Silva-Júnior, A. A., Araújo, A. A., Cruz, L. J., Chan, A. B., & de Araújo Júnior, R. F. STAT3/NF-κB signalling disruption in M2 tumour-associated macrophages is a major target of PLGA nanocarriers/PD-L1 antibody immunomodulatory therapy in breast cancer. Br J Pharmacol. 2021;178(11):2284-2304. doi:10.1111/bph.15373pt_BR
dc.identifier.doi10.1111/bph.15373
dc.identifier.urihttps://repositorio.ufrn.br/handle/123456789/49513
dc.languageenpt_BR
dc.publisherBritish journal of pharmacologypt_BR
dc.subjectImmunomodulationpt_BR
dc.subjectM2‐like macrophagespt_BR
dc.subjectNF‐κBpt_BR
dc.subjectPD‐L1 antibodypt_BR
dc.subjectPLGA nanoparticlespt_BR
dc.subjectSTAT3pt_BR
dc.subjecttumour microenvironmentpt_BR
dc.titleSTAT3/NF‐κB signalling disruption in M2 tumour‐associated macrophages is a major target of PLGA nanocarriers/PD‐L1 antibody immunomodulatory therapy in breast cancerpt_BR
dc.title.alternativeSTAT3/NF‐κB signalling disruption in M2 tumour‐associated macrophages is a major target of PLGA nanocarriers/PD‐L1 antibody immunomodulatory therapy in breast cancerpt_BR
dc.typearticlept_BR

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