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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

Cavalcante, Rômulo S. ; Ishikawa, Uta ; Silva, Emanuell S. ; Silva‐Júnior, Arnóbio A. ; Araújo, Aurigena A. ; Cruz, Luis J. ; Chan, Alan B. ; Araújo Júnior, Raimundo F.

British journal of pharmacology, 2021-06, Vol.178 (11), p.2284-2304 [Periódico revisado por pares]

England: Blackwell Publishing Ltd

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Título:
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
Autor: Cavalcante, Rômulo S. ; Ishikawa, Uta ; Silva, Emanuell S. ; Silva‐Júnior, Arnóbio A. ; Araújo, Aurigena A. ; Cruz, Luis J. ; Chan, Alan B. ; Araújo Júnior, Raimundo F.
Assuntos: Antibodies ; Breast cancer ; Caspase ; CCL22 protein ; CD163 antigen ; Cell culture ; Cell death ; Cell migration ; CXCR4 protein ; FADD protein ; Glycolic acid ; Hyaluronic acid ; Immune response ; Immunohistochemistry ; Immunomodulation ; Immunosuppression ; Inflammation ; Leukocyte migration ; M2‐like macrophages ; Macrophages ; Metastases ; Methotrexate ; Microenvironments ; Nanoparticles ; NF‐κB ; PD‐L1 antibody ; Phenotypes ; PLGA nanoparticles ; Polyethyleneimine ; Polylactide-co-glycolide ; Research Paper ; Research Papers ; STAT3 ; Stat3 protein ; Tumors ; tumour microenvironment
É parte de: British journal of pharmacology, 2021-06, Vol.178 (11), p.2284-2304
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SourceType-Scholarly Journals-1
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Descrição: Background 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.
Editor: England: Blackwell Publishing Ltd
Idioma: Inglês

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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

Cavalcante, Rômulo S. ; Ishikawa, Uta ; Silva, Emanuell S. ; Silva‐Júnior, Arnóbio A. ; Araújo, Aurigena A. ; Cruz, Luis J. ; Chan, Alan B. ; Araújo Júnior, Raimundo F.

England: Blackwell Publishing Ltd

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