Therapeutic Strategies to Interfere with Inhibition of Anti-tumor Immune Activity Mediated by Regulatory T cells

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Regulatory T cells (Tregs) represent a subset of CD4 T cells that have strong immune inhibitory properties and suppress the function of effector T cells. These cells accumulate in the vicinity of malignant tumors, draining lymph nodes and metastasis where they suppress the anti-tumor immune function. We wish to identify the molecular mechanisms Tregs employ to suppress effector T cells. This will allow therapeutic intervention blocking the immunosuppressive mechanisms and improving anti-tumor immune funct ion. Cyclic AMP acts as an acute inhibitor of T cell activation preventing T cell proliferation and cytokine production. We have discovered that adaptive Tregs formed upon chronic antigen stimulation express cyclooxygenase (COX)-2, secrete prostaglandin E 2 (PGE2) and suppress effector cells through cAMP. We have previously mapped a regulatory pathway in T effector cells that involves cAMP, protein kinase A (PKA) type I and C-terminal Src kinase (Csk) that strongly suppresses immune function. We show that this mechanism is active in suppressing anti-tumor immune responses ex vivo in patients with colorectal carcinoma. The overall aim of the present proposal is to investigate mechanisms of immune suppression by Tregs and the extent of involvement of the cAM P signalling pathway and other pathways in immune suppression of T effector cells by Tregs in anti-neoplastic immunity in various cancers. We wish to address a limited set of objectives that can be accomplished within the proposed framework and with integ ration of national and international collaborators and expertise in this area. This encompasses i) Identifying molecular mechanisms employed by Tregs in suppression; ii) Evaluation of the role of Tregs cells in suppressing anti-neoplastic immune function s using cells and tissues derived from surgical specimens and ascites from cancer patients; and iii) Development of new therapeutic strategies for treatment of cancer based on immunomodulation.