Abstract
Squamous cell carcinoma of the head and neck (HNSCC) is a locally invasive cancer with a poor prognosis when diagnosed in advanced stages. Survival rate in advanced cases is worse than breast or prostate cancer and its treatment is associated with severe morbidity. Response to treatment is highly variable even among patients in early stages of disease in spite of treatment according to standard-of-care guidelines. Therefore, there is great interest on the identification of biomarkers that indicate an aggressive phenotype and may provide information useful in novel targeted therapies. Changes in the cytokine profile in the plasma of HNSCC patients suggest a shift of the immune response to a T helper 2 (Th2) profile, with reduced interleukin (IL)-12 and increased IL-10 expression as HNSCC progresses from stages I/II to stages III/IV [1]. Moreover, the status of adaptive immune response has been related with outcome, as a higher percentage of CD8+ T cells were associated with better response to treatment and increased survival in advanced-stage HNSCC [2]. This information indicates a marked effect of HNSCC on the immune response, however there is a relative paucity of information on tumor-immune response interactions in HNSCC. Galanin, a small peptide originally associated with neuronal cell function, is highly expressed by some HNSCC cell lines. This peptide can engage three different receptors (GalR1, 2 and 3), which have varying levels of expression in HNSCC cells. In rat thymocytes, only GalR1 and GalR3 expression was detected, and stimulation of these cells with galanin decreased proliferation and increased apoptosis [3]; which in the context of HNSCC cells expressing high levels of galanin may represent an immune evasion mechanism. High galanin expression and increased galanin receptor 2 signaling result in increased proliferation, cytokine expression, invasion of HNSCC cells in vitro and also promotes tumor growth in vivo in the absence of T cells [4, 5]. After galanin binds to GalR2 in HNSCC cells, Rap1 (a GTP-binding protein) is activated and triggers a complex signaling network, including activation of MEK/ERK, PI3- kinase/Akt [4] and increased nuclear translocation and stability of b-catenin [6], which ultimately mediates the cellular changes in proliferation, survival, cytokine expression and invasion. In T cells, Rap1 plays a central role in cell adhesion upon engaging of T cell receptor [7], which may affect T cell migration to sites of inflammation, movement in the lymph nodes and conjugate formation between T cells and antigen-presenting cells (APCs). Activation of Rap1 in T cells induced by HNSCC-derived galanin and/or by G-coupled protein receptor-activating cytokines may generate a spectrum of immunological responses ranging from nonproductive responses to productive immunity and activation-induced cell death [8, 9]. The role of increased galanin expression by HNSCC cells on T cell response has not been investigated and the main hypothesis for this proposal is: increased expression of galanin by HNSCC cells is crucial on the modulation of adaptive immune response by these tumors. (AU)
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