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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

Grant number: 20/00394-2
Support type:Research Projects - Thematic Grants
Duration: September 01, 2021 - August 31, 2026
Field of knowledge:Health Sciences - Dentistry
Principal researcher:Carlos Rossa Junior
Grantee:Carlos Rossa Junior
Home Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Pesquisadores principais:
Debora Aparecida Pires de Campos Zuccari ; Eny Maria Goloni Bertollo
Assoc. researchers:Andreia Bufalino ; Arnaud Millet ; Chamindie Punyadeera ; Fabio Daumas Nunes ; Keith Lough Kirkwood ; Nisha Jacintha da Silva ; Ricardo Della Coletta

Abstract

Loco-regional invasion and metastasis are the major causes of morbidity and mortality in most solid tumors, including head and neck squamous cell carcinomas (HNSCC). The sustained incidence and shifting epidemiological profile of HNSCC associated with the poor and marginally improved 5-year survival rates, high recurrence and severe functional and psychological negative consequences affecting the survivors' quality of life supports the need for novel therapeutic approaches aimed at reducing invasion and metastasis. In the past two decades, interest in the tumor microenvironment (TME) has surged due to the increased acknowledgment of the relevant roles of non-neoplastic cells and extracellular matrix on the initiation and progression of solid tumors. Recently, research in tumor immunology yielded novel therapeutic approaches incorporated into the clinical management of various cancers, including HNSCC. These approaches are derived from promising results of in vitro and pre-clinical studies; however, they have shown variable clinical responses, ranging from complete and durable remissions to partial responses and even the paradoxical hyperprogression. This limited clinical translation may be associated with the complexity of the immunological landscape of the TME, including amount of infiltrating immune cells, their type, phenotype and spatial distribution. These variations may be associated with intrinsic (e.g., mutagenic load, antigenicity) and/or extrinsic (e.g., expression of immunosuppressive mediators) of the neoplastic cells, mediating the "dialogue" with immune cells in the TME. Macrophages are the most abundant immune cells in the TME of HNSCC and are strongly associated with prognosis and response to treatment through their role in the degradation of extracellular matrix and angiogenesis; in addition to their role in activating and modulating the phenotype of T cells. There is evidence indicating that macrophages can have their phenotype modulated in the TME and may be co-opted to enhance tumor invasion and dissemination. Incipient evidence indicates that macrophages may be involved in the hematogenic dissemination via CTCs (circulating tumor cell clusters). This proposal intends to investigate the influence of GALR2 as a biomarker of tumor aggressiveness and immunosuppression; and also of efferocytosis as a immunosuppressive process in the TME. The experimental approaches will allow for the investigation of the relevance of these two immunosuppressive biological processes independently and concomitantly on tumor invasion and dissemination. The proposed experiments include in vitro studies and various in vivo models for experimental intervention, and the use of HNSCC patient-derived samples for ex-vivo analyses of association and intervention The ultimate goal of this proposal is to provide information on the potential of novel therapeutic approaches that may be subsequently investigated in clinical studies. (AU)

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