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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA175495-01A1
Application #
8631219
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
10461
Picarda, Elodie; Ohaegbulam, Kim C; Zang, Xingxing (2016) Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy. Clin Cancer Res 22:3425-31
Cheng, Haiying; Janakiram, Murali; Borczuk, Alain et al. (2016) 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 :
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
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
Yao, Yu; Ye, Hongxing; Qi, Zengxin et al. (2016) B7-H4(B7x)-Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients. Clin Cancer Res 22:2778-90
Janakiram, Murali; Chinai, Jordan M; Zhao, Aimin et al. (2015) HHLA2 and TMIGD2: new immunotherapeutic targets of the B7 and CD28 families. Oncoimmunology 4:e1026534
Subramaniam, Krishanthi S; Spaulding, Emily; Ivan, Emil et al. (2015) The T-Cell Inhibitory Molecule Butyrophilin-Like 2 Is Up-regulated in Mild Plasmodium falciparum Infection and Is Protective During Experimental Cerebral Malaria. J Infect Dis 212:1322-31
Zhao, Hongling; Bauzon, Frederick; Bi, Enguang et al. (2015) Substituting threonine 187 with alanine in p27Kip1 prevents pituitary tumorigenesis by two-hit loss of Rb1 and enhances humoral immunity in old age. J Biol Chem 290:5797-809
Assal, Amer; Kaner, Justin; Pendurti, Gopichand et al. (2015) Emerging targets in cancer immunotherapy: beyond CTLA-4 and PD-1. Immunotherapy 7:1169-86
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

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