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 Opportunities: Research Projects - Thematic Grants
• Start date: September 01, 2021
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Carlos Rossa Junior
• Grantee: Carlos Rossa Junior
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Pesquisadores principais:( Atuais ): Eny Maria Goloni Bertollo
• Pesquisadores principais:( Anteriores ): Debora Aparecida Pires de Campos Zuccari
• Associated researchers: Andreia Bufalino ; Arnaud Millet ; Chamindie Punyadeera ; Fabio Daumas Nunes ; Keith Lough Kirkwood ; Nisha Jacintha da Silva ; Ricardo Della Coletta
• Associated research grant(s): 21/13342-3 - Multi-user equipment approved in grant 2020/00394-2: Flow Cytometer, AP.EMU
• Associated scholarship(s): 24/01910-5 - Expression of interleukin-4-induced gene-1 (IL4I1) in head and neck squamous cell carcinoma (HNSCC) and its association with macrophage infiltration, tumor staging and efferocytosis, BP.IC; 23/12519-2 - Association between expression of GALR2/Galanin and chemokine/chemokine receptors and leukocyte infiltration in head and neck squamous cell carcinoma, BP.IC; 23/08477-2 - Investigation of the immune response pattern of athymic mice in heterotopic xenograft models of Oral Carcinoma: influence of functional inhibition of GALR2, BP.PD; + associated scholarships 22/05120-3 - NLRP3 inflammasome and progression of Oral Squamous Cell Carcinoma (OSCC): differential influence in neoplastic and immune cells, BP.DR; 22/01487-0 - AXL receptor in myeloid cells and the immunosuppressive / efferocytosis loop in oral squamous cell carcinoma, BP.DR; 22/11191-0 - Association between GALR2 and efferocytosis markers with presence of Tertiary Lymphoid Structures (TLS) and immune response profile in OSCC patients: interaction between immunosuppressive biological aspects and tumor aggressiveness, BP.DD; 22/06041-0 - Efferocytosis in the microenvironment of Oral Squamous Cell Carcinoma: impact on immune response and tumor progression and dissemination, BP.PD; 22/01484-0 - Influence of Tregs on the phenotype of monocytes/macrophages in the tumor microenvironment and on response of Oral Squamous Cell Carcinoma to cytotoxic chemotherapy, BP.DR; 22/01681-0 - Extracellular fibronectin influences on OSCC migration, invasion and macrophage phenotype, BP.IC; 22/01041-1 - Influence of efferocytosis of HNSCC cells on macrophage phenotype, BP.DD; 22/01672-1 - Monocyte invasion in the 3D microenvironment of tongue Câncer cells: influences on differentiation and phenotype, BP.IC; 22/00890-5 - Investigation of immune response in C57Bl/6 and Balb/c athymic mice in oral carcinoma heterotopic xenograft models: the influence of GALR2 functional inhibition, BP.PD - associated scholarships

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)