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Galanin and galanin receptor 2 (GalR2) as mediators of the activation of inhibitory immunological checkpoints PD-1/PD-L1 and CTLA4/B7-1 by squamous cell carcinoma of the tongue and oropharynx

Grant number: 16/10778-7
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2016
Effective date (End): April 21, 2019
Field of knowledge:Health Sciences - Dentistry
Principal researcher:Morgana Rodrigues Guimarães Stabili
Grantee:Marcell Costa de Medeiros
Home Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Each year 600,000 individuals are diagnosed with head and neck squamous cell carcinoma (HNSCC), the eigth most common type of cancer worldwide, with a 5-year survival rate below 50% in advanced cases. Treatment of HNSCC had no major progress in the past 4 decades, with surgical resection with/without radiotherapy or radio-chemotherapy still the most frequent treatment approaches, which is not only of limited success in advanced cases, but also associated with high morbidity for the patients. The identification of diagnostic markers or prognosis in HNSCC is hampered by the heterogeneity of these tumors. This heterogeneity includes variations in the etiopathogenesis, phenotypical characteristics and response to treatment, which currently motivates the questioning of the common 'HNSCC' denomination, based solely on the anatomical location of the primary lesion. Galanin is a peptide of 29 amino acid residues originally identified as a neuropeptide, but widely distributed in the body and broad spectrum of biological effects. Increased signaling via GalR2, has been shown to promote tumor growth, which supports a role for this receptor (and for increased galanin production) as a marker of tumor aggressiveness and of poor prognosis; and also as a possible therapeutic target. Recently, there has been great interest in studying the interaction of tumors with the immune system, in order to rescue or enhance anti-tumor immune activity. The most explored approach is the inhibition pro-tumorigenic aspects of tumor-induced inflammation, notably the release of the immune response from the constraints of inhibitory immunological checkpoints PD-1/PD-L1 and CTLA4/B7-1, which has been intensely studied even in clinical trials. Preliminary studies indicate a novel role of galanin as activator of PD-1/PD-L1 inhibitory immunological checkpoint by inducing PD-L1 (B7H1) expression in tumor cells. We have also observed the suppressive effects of galanin and tumor-derived soluble products on immune cells, which may involve the activation of the inhibitory checkpoint CTLA4/B7-1. Considering: 1) the immunosuppressive effects of products secreted by oral cancer cell lines; 2) the supporting data indicating that galanin has immunosuppressive effects on immune cells; and based on preliminary data indicating the new role of galanin as a modulator PD-L1 expression, the purpose of this study is to evaluate the possible involvement of galanin and of the activity of GalR2 on the activation of PD-1/PD-L1 and CTLA4 / B7-1 inhibitory checkpoints. Our main hypothesis is that tumor-derived galanin activates, directly or indirectly, the inhibitory immunological checkpoints PD1/PD-L1 and CTLA-4/B7-1.