Secreted products from oral squamous cell carcinoma cells, galanin and GalR2 activity influence on the phenotype and cytotoxic activity of CD8+ cells

Abstract

Each year 600,000 individuals are diagnosed with head and neck squamous cell carcinoma (HNSCC), which is the eight most common type of cancer worldwide, with an overall 5-year survival rate below 50%, and in cases diagnosed in advanced stages the survival rate is as low as 20%. Treatment of HNSCC had no significant progress in the past 4 decades, and the surgical resection with/without radiotherapy or radio-/ chemotherapy-based treatment is still the gold standard, which is usually associated with high morbidity. The identification of diagnostic markers or prognosis in HNSCC is also hampered by the heterogeneity of these tumors. This heterogeneity includes variations in etiopathogenesis, phenotype and response to treatment, which currently questions the 'HNSCC' denomination based 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 with a broad spectrum of biological effects. Increased signaling via GalR2 has been shown to promote tumor growth, which supports expression of this receptor as a marker of tumor aggressiveness and also as a possible therapeutic target to inhibit progression of HNSCC. Recently there has been great interest in studying the interaction of tumors with the immune system, in order to recover or enhance anti-tumor immune activity or to inhibit pro-tumor specific aspects of tumor-induced inflammation. Preliminary studies indicate a novel role of galanin as an activator of endogenous inhibitory mechanisms in immune cells (immunological checkpoints), such as PD-L1/PD-1. Activation of these inhibitory immunological checkpoints can inhibit the activation, effector function and even lead to apoptosis of T cells. Considering 1) the immunosuppression associated with HNSCC; and 2) the identification of galanin/GalR2 activity in tumor cells as an immunosuppressive mechanism, the purpose of this study is to determine the role of cancer cell-secreted products and the specific involvement of galanin and GalR2 in tumor cells on the phenotype and cytotoxic activity of CD8+ cells.