Study the role of B cell in regulation of anti-tumor response in solid tumor. Identify a subset of the B regulatory cells in the solid tumor and their phenotype and function in suppressing T cell anti-tumor response. In mouse model, B cells upon migration into tumor microenvironment and in contact with tumor cells become suppressor cells like T regulatory cells, we named that subset of B cells as B regulatory cells (Breg cells). This type of B cells over-express inhibitory co-stimulatory molecules, such as CD86, PD-L1, B7-H2, and membrane-bound TGF-b. These Bregs suppressed CD4 and CD8 T cell activation, proliferation and Th1 cytokine secretion in vitro and in vivo. Similar Breg activity may be identified in human solid tumors as well as lymphoid malignancies. Whether Breg populations could be targeted in an effort to enhance anti-tumor T cell responses requires better definition of the immune suppressive Breg population in man.
Our laboratory has been focused on the use of antibody engineering to develop bifunctional molecules which employ antibody to target additional biological effector molecules to the site of micrometastatic disease. Our main efforts have concentrated on targeting of anti-angiogenic factors and immune effector molecules such as chemokines and co-stimulatory ligands in order to improve their biological efficacy. Our approach has been to combine anti-angiogenic peptides such as endostatin with targeting specificity of an anti-tumor antibody. We have constructed several antibody-endostatin fusion proteins by linking human endostatin (wild type and mutant P125A type) to human IgG antibodies directed at validated solid tumor antigens such as HER2 and EGFR. Our research goal is to develop therapeutic anti-tumor antibody fusion proteins, which employ the targeting flexibility of antibodies to direct localization of biological active molecules to the tumor site, and to investigate mechanisms of anti-tumor efficacy of such reagents in preparation for potential human use. Our bifunctional molecules demonstrate unique anti-tumor efficacy in mouse models and possess the ability to inhibit both angiogenesis and vasculogenic mimicry. We will investigate mechanisms by which antibody-endostatin fusion proteins inhibit endothelial angiogenesis and/or vasculogenic mimicry and oversee studies of efficacy of antibody-endostatin fusion proteins used alone or in combination in preclinical models.