Title of Abstract
The goal of cancer immunotherapy is to induce tumor-specific immune responses while limiting off-target damage to normal tissues in the host. Temporal and tissue-specific modulation of co-stimulatory and co-inhibitory pathways that regulate T-cell activation in response to tumor-specific antigens and antigens expressed on host epithelial cells offers a strategy to activate cancer-specific T-cells while limiting auto-immunity. Vasocactive intestinal polypeptide (VIP) is an immunosuppressive neuropeptide secreted by lymphocytes and non-lymphoid cells that binds to G-coupled protein receptors: VPAC1 and VPAC2 expressed on T-cells and dendritic cells (DC). VIP signaling in T-cells induces CD152 expression, and promotes Treg development; VIP signaling in DC down-regulates expression of CD80 and CD86 on during inflammation, generating tolerogenic DCs that limit T cell activation. We have studied the role of VIP signaling during immune responses and shown VIP expression it is sequentially up-regulated in T cells and DC cells during activation of antigen-specific T cells. Treating tumor-bearing animals with an inhibitor of VIP signaling induced robust oligoclonal responses that eliminated cancer with limited off-target immune effects. Tumor protection was dependent upon the presence of CD8+ T cells and could be adoptively transferred to secondary recipients. T cells cultured with VIPhyb, an antagonist of VIP signaling, and idelalisib, a PI3K inhibitor, had three-fold increased net expansion and increased frequencies of naïve and central memory T cells. VIPhyb/PI3Ki enhanced cultured rescued senescent T cells from heavily pre-treated lymphoma patients and T cells cultured with VIPhyb/PI3Ki persisted in vivo in NSG mice following adoptive transfer while conventionally-expanded T cells did not. Taken together these studies indicate a central role for VIP signaling during adaptive immune responses to cancer and indicate that pharmacological targeting of this pathway can induce robust anti-cancer immunity in vivo and enhance ex vivo expansion of CAR T cells.
Dr. Waller’s research focus is in enhancing immune reconstitution after stem cell transplant and developing cell therapy for anti-tumor immunology and in regenerative medicine. His current research activities include pre-clinical and clinical studies focused on the role of donor immune cells in optimizing anti-tumor immunity after allogenic transplantation, and the clinical application of autologous CD34+ cells in improving vascular function and facilitating neo-angiogenesis in patients with peripheral and coronary vascular disease. His NIH-funded basic research lab uses mouse models and performs immunological analyses of clinical samples from patients. He has active translational research activities and serves as a principal investigator on institutional and national cooperative group clinical trials.
Edmund K. Waller; Chris Petersen; Jian Ming Li; Cindy Giver; Yiwen Li; Yitong Wang; Moji Hassan
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