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Influence of efferocytosis of HNSCC cells on macrophage phenotype

Grant number: 22/01041-1
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): April 01, 2022
Effective date (End): March 31, 2025
Field of knowledge:Health Sciences - Dentistry
Principal Investigator:Carlos Rossa Junior
Grantee:Danilo Paschoal Ferrarezi
Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Associated research grant:20/00394-2 - Head and neck squamous cell carcinoma (HNSCC) invasion and distant metastasis: relevance and crosstalk between GALR2 and efferocytosis in the tumor microenvironment and hematogenic dissemination, AP.TEM

Abstract

Efferocytosis is likely to be highly active in the Tumor Microenvironment (TME) of HNSCC, as apoptosis is a frequent event, either as a result of hypoxia/metabolic changes in growing/untreated tumors or as a result of treatment (chemoradiotherapy). Macrophages are the most abundant immune cell type in the TME, in which these cells are called Tumor-Associated Macrophages (TAM). Increased prevalence of TAMs with a M2-like phenotype are associated with poorer outcomes in HNSCC; and macrophages are the prototypical phagocytosing/efferocytotic cell type. Efferocytosis is considered an immunologically silent process, which is more efficiently carried out by M2-type (alternatively activated) macrophages. Importantly, in physiological conditions efferocytosis further skews macrophages to the M2 phenotype, associated with increased production of MMPs, angiogenic factors and immunosuppressive cytokines. These changes in macrophage biology may favor tumor progression. The purpose of this study is to assess in vivo (nude mice xenograft model), in vitro (3D spheroid co-cultures of macrophages and HNSCC cells) if inhibition of efferocytosis reduces tumor invasion and lymph node metastasis of HNSCC. Macrophage phenotype will be investigated by expression of M1/M2 markers and by transcriptomic analysis (Nanostring nCounter) and also by immunohistochemistry. Apoptosis will be induced in vitro by exposure to a empirically-determined titrated concentration of 5-FU that induces 30-60% apoptosis in 24 h, whilst in vivo (nude mice model) by a combination of cisplatin (2mg/Kg) and 5-FU (25 mg/Kg) administered via i.p. (Q7dx2). Efferocytosis will be inhibited in vitro and in vivo by antibodies blocking the recognition of phosphatidylserine on the membrane of apoptotic cells by the efferocytotic cells (Bavituximab, Creative Biolabs) or by blocking RAC1 (Tocris Bioscience). The central hypothesis in this project is that in the TME of HNSCC, efferocytosis enhances macrophage-facilitated tumor invasion and metastatic dissemination. (AU)

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