Accumulating clinical evidence has made immunotherapy of cancer as a very promising therapeutic strategy. However, the highly immune suppressive nature of the tumor microenvironment has been the main challenge for such approach. Within the tumor microenvironment, the lack of proper immune stimulatory signals results in unsupported tumor immunosurveillance and eventual dominance of tumor promoting inflammation. Our long term goal is to discover critical inflammatory signals that can promote anti-tumor cell-mediated immune responses and alter tumor microenvironment to one that favors tumor eradication. Interleukin-33 is a member of the IL-1 family of cytokines and is released by necrotic cells or activated innate immune cells such as macrophages during trauma or infection. Thus, IL-33 is thought to serve as an endogenous """"""""danger signal"""""""" to trigger inflammation and promote cell-mediated immune responses. Prior studies have supported the role of IL-33 in promoting Th2 as well as Th1 immune responses. Whether IL-33 is involved in anti-tumor immune response is unclear. We have recently found that IL-33 is expressed in macrophages isolated from tumors responsive to vaccine. Our study has further revealed that ST2, a receptor for IL-33, is highly expressed in CD8 tumor infiltrating lymphocytes (TILs) as well as CD8 T cells cultured in Th1 conditions. More interestingly, we have demonstrated that T-bet, a critical transcriptional factor of the Th1 differentiation is required for ST2 expression by CD8 T cells, suggesting ST2 is an integral part of the Th1 program in CD8 T cells. Importantly, we have demonstrated that IL-33 synergized with TCR or IL-12 in increasing both human and mouse CD8 T cell functions such as IFN production. The expression of IL-33 in B16 melanoma cells potently inhibits tumor growth in mice without affecting B16 proliferation in vitro. Moreover expression of IL-33 induced changes in the cellular components of the tumor microenvironment that favor tumor eradication. We hypothesize that the expression of immunological """"""""danger signal"""""""" IL-33 in the tumor environment promotes Tc1 immune responses against cancer. Following aims are proposed to test this hypothesis:
Specific Aim 1. To determine whether IL-33 inhibits tumor growth through CD8 T cells in vivo.
Specific Aim 2. To determine the role of IL-33 in adoptive T cell therapy of an established tumor. Our study will reveal how IL-33 promotes anti-tumor immune responses, and represents a novel anti-tumor pathway. IL-33 stands out as a new candidate tumor therapeutic cytokine because it can directly enhance the function of anti-tumor CD8 T cells and also alter the tumor microenvironment to allow more effective antitumor immune responses. Our finding that """"""""danger signal"""""""" cytokine IL-33 can promote TC1 function will provide a new immune stimulatory pathway for enhancing CD8 T cell responses against tumor cells.

Public Health Relevance

Our finding that danger signal cytokine IL-33 can promote TC1 function will provide a new immune stimulatory pathway for enhancing CD8 T cell responses against tumor cells. Such studies will significantly improve our knowledge about anti-tumor immunity and will provide insights with potential applications in novel treatments. A clear mechanistic study will pave way for further clinical translation of using IL-33 in tumor immunotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Mccarthy, Susan A
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University of Pittsburgh
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