The B7x pathway in the tumor microenvironment One of the key issues in cancer immunotherapy is to identify the dominant escape mechanisms during different phases of tumor growth and to devise ways to overcome them. We have identified B7x as a poorly characterized member of the B7 family of T cell costimulation and coinhibition. Our clinical data have revealed that aberrant expression of B7x is observed in a variety of human cancers and is often associated with poor clinical outcome. The hypothesis of this project is that B7x is a critical immune evasion pathway within the tumor microenvironment and blockade of this pathway generates therapeutic tumor immunity. Guided by our published clinical research with cancer patients and our strong preliminary data with murine tumor models, this hypothesis will be tested by pursuing three specific aims: 1) Elucidation of the functional consequence of tumor-expressed B7x in disease progression;2) Determination of mechanistic contribution of host cell-expressed B7x to tumor progression;and 3) Generation of therapeutic tumor immunity by targeting the B7x pathway. We have generated a number of novel tools and have assembled a multi-disciplinary team with complementary skill sets, which provides us with unique opportunities to address challenges and realize goals. The outcomes of this research will provide novel insights into immune evasion mechanisms of the B7x pathway in the tumor microenvironment and provide the basis for future clinical design of a new immunotherapy.

Public Health Relevance

The proposed research is relevant to public health and NIH's mission, because our program will not only define a dominant escape mechanism within tumor microenvironment but also translate to new therapy opportunities for cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Mccarthy, Susan A
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Albert Einstein College of Medicine
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Cheng, Haiying; Borczuk, Alain; Janakiram, Murali et al. (2018) Wide Expression and Significance of Alternative Immune Checkpoint Molecules, B7x and HHLA2, in PD-L1-Negative Human Lung Cancers. Clin Cancer Res 24:1954-1964
Sankin, Alexander; Narasimhulu, Deepa; John, Peter et al. (2018) The expanding repertoire of targets for immune checkpoint inhibition in bladder cancer: What lies beneath the tip of the iceberg, PD-L1. Urol Oncol 36:459-468
Ohaegbulam, Kim C; Liu, Weifeng; Jeon, Hyungjun et al. (2017) Tumor-expressed immune checkpoint B7x promotes cancer progression and antigen-specific CD8 T cell exhaustion and suppressive innate immune cells. Oncotarget 8:82740-82753
Janakiram, Murali; Shah, Urvi A; Liu, Weifeng et al. (2017) The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3. Immunol Rev 276:26-39
Cheng, Haiying; Janakiram, Murali; Borczuk, Alain et al. (2017) HHLA2, a New Immune Checkpoint Member of the B7 Family, Is Widely Expressed in Human Lung Cancer and Associated with EGFR Mutational Status. Clin Cancer Res 23:825-832
Koirala, Pratistha; Roth, Michael E; Gill, Jonathan et al. (2016) Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. Sci Rep 6:30093
Liu, Weifeng; Almo, Steven C; Zang, Xingxing (2016) Co-stimulate or Co-inhibit Regulatory T Cells, Which Side to Go? Immunol Invest 45:813-831
Janakiram, Murali; Pareek, Vipul; Cheng, Haiying et al. (2016) Immune checkpoint blockade in human cancer therapy: lung cancer and hematologic malignancies. Immunotherapy 8:809-19
Koirala, Pratistha; Roth, Michael E; Gill, Jonathan et al. (2016) HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival. Sci Rep 6:31154
Picarda, Elodie; Ohaegbulam, Kim C; Zang, Xingxing (2016) Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy. Clin Cancer Res 22:3425-3431

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