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The prognosis of ovarian cancer is positively correlated with tumor infiltration of effector T cells. Activation of effector T cell depends on the balance between co-stimulatory and inhibitory signals that are mainly delivered by antigen presenting cells, including macrophages and B cells. The Scholler's laboratory studies the mechanisms controlling the inhibition of T cell-mediated anti-tumor responses in ovarian cancer, with a particular interest for tumor-associated macrophages (TAMs) and tumor-associated B cells.
To characterize the tumor immune infiltrate in vivo, we have been using syngeneic, transgenic, and humanized mouse models of serous ovarian cancer. We discovered that complement activation is critical for ovarian tumor growth and that tumor-associated B lymphocytes exhibit various tumor promoting functions. We are currently completing the functional characterization of ovarian tumor infiltrating B cells. Given the role of macrophages in tumor growth, T cell co-stimulation, and their temporal association with B-cell tumor-infiltration, we also develop tools to repolarize tumor macrophages, including recombinant antibodies (scFv). This work could lead to a novel therapeutic strategy able to redirect the tumor microenvironment toward an anti-tumor response by stabilizing the phenotype of M1 macrophages.
Building on our long-standing expertise in the field of antibody development, we have created two new libraries of yeast-display scFv derived from human patients with autoimmune disease (TTP, in collaboration with Dr Siegel) or with ovarian cancer. Screening these libraries, we have identified several target-specific scFv, including anti-tumor vasculature marker (TEM1), anti-B7H4, and anti-mannose receptor/CD206 scFvs. We are pursuing these important newly developed tools in different clinically relevant applications in collaboration with several laboratories at Penn and outside Penn: functionalizing nanoparticles for organ-specific delivery of nucleic acids; contrast imaging agents and/or cytotoxic reagents; and physically active nanoparticles such as nanorods. ScFv are also being tested for direct radiolabelling and generation of T-cells redirected to target through scFv. The lab is currently invested in deriving additional scFv against critical tumor-associated targets and to test their application in concrete disease models including ovarian and breast cancers.