Cross-talk between cancer and immune cells in oral squamous cell carcinoma invasion and metastasis: study in a novel in vivo model

Abstract

Oral squamous cell carcinoma, the most common type of oral cancer (OC), has a poor prognosis. Almost half of the patients die within five years of diagnosis. Response to therapy is highly variable even among patients with early stage OC. This highlights the importance of identifying biomarkers to predict response to treatment and also novel potential treatment targets and strategies. From a clinical perspective, metastasis and invasion are the most critical aspects of cancer progression, since over 90% of the mortality is caused by metastasis. The host immune response to OC is prognostic of the tumor's behavior. Targeting immunologic pathways is of emerging importance in the development of novel therapies for OC. Given the heterogeneity of OC, it is likely that multiple immunologic pathways regulate tumor progression. Recent studies by the collaborator in this proposal have demonstrated that the G-protein coupled receptor, galanin receptor 2 (GALR2), has an important role in OC progression via secretion of cytokines. In collaborative studies, we have shown that GALR2 modulates proliferation and phenotype of immune cells. The goal of this present proposal is to address the mechanism by which OC modulates the immune response via GALR2 to promote evasion of immunosurveillance and tumor invasion and metastasis. The hypothesis is that increased activation of GALR2 in cancer cells influences the tumor microenvironment making it conducive for tumor progression via autocrine effects on the tumor cells themselves and also through paracrine effects on immune cells in the tumor microenvironment, affecting the plasticity of the immune response. The rationale of this proposal is that elucidation of a galanin/GALR2-associated mechanism of immune evasion will identify new therapeutic targets for rescuing anti-tumor immune plasticity. We will test the main hypotheses by pursuing the following aims: #1) to determine the relevance of GALR2 activity in cancer cells for tumor invasion and metastasis in the presence of immune cells in vivo; and #2) to investigate the mechanism of GALR2-mediated immune modulation on tumor progression in vivo. The proposed studies will investigate an important but understudied area of tumor progression.