B7-H1 (PD-L1) and its receptor PD-1 are checkpoint molecules in immune system. Elevated B7-H1 expression on tumor cells has been correlated with poor prognosis in several human cancer diseases. Preliminary clinical observations show promising therapeutic effects of B7-H1 blockade in treating advanced human solid tumors (lung cancer, melanoma and kidney cancers). However, only a small portion of patients have long lasting objective responses, although prolonged stabilization of diseases is observed in 12-41% of treated patients. Our compelling preliminary studies suggest that unanticipated disrupting of a previously unknown pro-survival function of B7-H1 expressed by T cells could be the major impediment to effective blockade therapy. The objective of this application is to define T cell intrinsic function of B7-H1 evaluate the impact of B7-H1 antibody capable of disrupting B7-H1's intrinsic function. The central hypothesis of this proposal is that B7-H1 has an intrinsic pro-survival function in activated CD8 T cells and is required for establishing protective immunity, B7-H1 antibody capable of disrupting this function compromises CD8 T cell-mediated antitumor immunity. The clinical impact of this proposal is that it may provide new knowledge and methods for maximizing B7-H1 blockade therapy by selection of optimal antibody. The rationale of this proposal is that the functional role of B7-H1 expressed by T cells is far from complete. Given that T cells are major effectors of immunity and B7-H1 expression on T cells is not static and varies with activation statuses warrants investigations into the significance of T cell-associated B7-H1 in greater detail. This issue becomes even more urgent since systemic antibody- mediated blockade of B7-H1 is being used in a multiple center phase I/II cancer immunotherapy trials. Thus, the proposed research is relevant to the mission of the NIH to develop new approaches in tumor immunotherapies. Supported by solid preliminary data, our hypothesis will be tested by pursuing three specific aims: (1) To define the role of T cell intrinsic B7-H1 in T cel differentiation;(2) To evaluate the impact of B7-H1 antibody on intrinsic function of B7-H1 in T cells;(3) To define the intrinsic signaling pathway of B7-H1 in T cell apoptosis. The proposed research is significant because our studies will provide new knowledge about regulation of T cell survival and provide new approaches in advancing the fields of B7 family checkpoint molecules and tumor immunotherapy.

Public Health Relevance

Checkpoint blockade therapy, especially those targeting B7-H1, has yielded promising therapeutic effects in treatment of human cancers. We have gathered preliminary data demonstrating that B7-H1 possesses a capacity to deliver novel signaling in T cells. Our proposal outlines experimentation directed towards developing a more thorough understanding of the function of B7-H1 in T cells. It is anticipated that knowledge gained from that line of investigation will have direct translational value by identifying new approaches for maximizing checkpoint blockade.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Lapham, Cheryl K
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Mayo Clinic, Rochester
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Yan, Yiyi; Cao, Siyu; Liu, Xin et al. (2018) CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. JCI Insight 3:
Yan, Yiyi; Kumar, Anagha Bangalore; Finnes, Heidi et al. (2018) Combining Immune Checkpoint Inhibitors With Conventional Cancer Therapy. Front Immunol 9:1739
Tang, Haidong; Liang, Yong; Anders, Robert A et al. (2018) PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest 128:580-588
Pavelko, Kevin D; Bell, Michael P; Harrington, Susan M et al. (2017) B7-H1 Influences the Accumulation of Virus-Specific Tissue Resident Memory T Cells in the Central Nervous System. Front Immunol 8:1532
Ni, Xiong; Song, Qingxiao; Cassady, Kaniel et al. (2017) PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells. J Clin Invest 127:1960-1977
Dong, Haidong; Yan, Yiyi; Dronca, Roxana S et al. (2017) A T cell equation as a conceptual model of T cell responses for maximizing the efficacy of cancer immunotherapy. SOJ Immunol 5:1-5
Dronca, Roxana S; Mansfield, Aaron S; Park, Sean S et al. (2016) BCL-2-interacting mediator of cell death (Bim) is a novel biomarker for response to anti-PD-1 therapy in patients with advanced melanoma. Immunotherapy 8:1351-1353
Liu, Xin; Wu, Xiaosheng; Cao, Siyu et al. (2016) B7-H1 antibodies lose antitumor activity due to activation of p38 MAPK that leads to apoptosis of tumor-reactive CD8+ T cells. Sci Rep 6:36722
Dronca, Roxana S; Liu, Xin; Harrington, Susan M et al. (2016) T cell Bim levels reflect responses to anti-PD-1 cancer therapy. JCI Insight 1:
Yin, Peng; Liu, Xin; Mansfield, Aaron S et al. (2016) CpG-induced antitumor immunity requires IL-12 in expansion of effector cells and down-regulation of PD-1. Oncotarget 7:70223-70231

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