The B7 family consists of structurally related protein ligands, which bind to the CD28 family of receptors on lymphocytes to regulate the immune response via co-stimulatory or co-inhibitory signals. It is the engagement of the T-cell receptor with specific cell surface antigen that initiates the first step of lymphocyte activation, but an additional signal delivered simultaneously by B7 ligands determines the ultimate fate of the immune response. B7x (B7-H4 or B7S1), a poorly characterized B7 family member, is expressed on immune cells, non- lymphoid tissues, and nearly all human tumor types and acts to down-regulate immune responses by inhibiting cell cycle progression, proliferation, and pro-inflammatory cytokine production of activated CD4+ and CD8+ T cells. B7x has been observed in cancer patients of nearly all types and this expression correlates positively with cancer staging, probability of recurrence, and negatively with survival, leading ultimately to poor clinicl outcomes. Currently, the mechanism B7x utilizes to generate inhibition of anti-tumor immunity remains elusive. The goal of this project is to reveal the physiological role of tumor expressed B7x in murine cancer models and generate anti-tumor immunity with a B7x-specific monoclonal antibody. We propose to accomplish these objectives by injecting B7x-positive and B7x-negative murine tumor cell lines into mice and monitoring the tumor growth and evolution of the immune reveal the physiological role of tumor expressed B7x in murine cancer models and generate anti-tumor immunity with a B7x-specific monoclonal antibody. We propose to accomplish these objectives by injecting B7x-positive and B7x-negative murine tumor cell lines into mice and monitoring the tumor growth and evolution of the immune response between both groups of mice. response between both groups of mice. We will then create a B7x-specific transgenic pancreatic cancer mouse model to evaluate the role of B7x in spontaneous tumorigenesis. Furthermore, we plan to evaluate the novelty of B7x as a target for immunotherapy by evaluating the efficacy of our newly generated anti-B7x specific monoclonal antibodies in generating anti- tumor immunity. We believe this project fully aligns with the missions of the National Cancer Institute because it will provide much needed insight into the mechanisms of B7x immune evasion in the cancer-associated pathway and highlights B7x as a viable and novel therapeutic target to increase overall improvement in patient outcome.
Cancer development and growth depends on the ability of tumor cells to express and/or secrete proteins that allow evasion of the host's immune system. B7x is a newly discovered protein expressed by nearly all human cancers that correlates with distant metastases, shorter survival time, and a poor clinical outcome through an undiscovered mechanism. This study proposes to reveal the mechanism of B7x in the cancer associated pathway and feature B7x as a novel target for immunotherapeutic manipulation to improve the anti-tumor immune response.
|Janakiram, Murali; Chinai, Jordan M; Fineberg, Susan et al. (2015) Expression, Clinical Significance, and Receptor Identification of the Newest B7 Family Member HHLA2 Protein. Clin Cancer Res 21:2359-66|
|Ohaegbulam, Kim C; Assal, Amer; Lazar-Molnar, Eszter et al. (2015) Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med 21:24-33|
|Jeon, Hyungjun; Vigdorovich, Vladimir; Garrett-Thomson, Sarah C et al. (2014) Structure and cancer immunotherapy of the B7 family member B7x. Cell Rep 9:1089-98|