Hui Hu, PhD
The Wistar Institute Cancer Center (Philadelphia, PA)
A novel T cell quiescence mechanism in anti-ovarian tumor responses.
Ovarian cancer is one of the deadliest cancers, responsible for the deaths of ~15,000 Americans per year, even more than melanoma, AML or brain tumors. 5-year survival rates have improved little in the last 30 years, and still remain at 30% at best for patients with metastatic ovarian carcinoma, the stage at which most cases are diagnosed. Studies using pre-clinical models indicate that tumor-reactive T cells properly conditioned ex vivo have the capacity to induce significant therapeutic effects against established ovarian cancer, yet the activity of transplanted T cells was suboptimal.
Novel strategies for reprogramming adoptively transferred anti-tumor T cells, to allow better engraftment and thus superior therapeutic activity in the especially hostile microenvironment of ovarian cancer, are urgently needed. Forkhead box (FOX) proteins are a large family of transcription factors with diverse functions in development, cancer, and aging. Recently we have demonstrated that Foxp1 exerts a novel cell-intrinsic regulation of T cell quiescence.
In a mouse model of ovarian carcinoma, which recapitulates the microenvironment of solid human ovarian cancers, we find that tumor-associated T cells up-regulate Foxp1 as the tumor progresses. We also find that Foxp1 dampens T cell immune responses. Therefore, in this proposal, we hypothesize that the up-regulation of Foxp1 in ovarian cancer-infiltrating T cells negatively regulates the T cell responses; consequently, Foxp1-deficient tumor-reactive T cells will better resist tumor-induced immunosuppressive signals and elicit superior anti-tumor immunity.
While we aim to determine the role of Foxp1 in tumor-induced T cell unresponsiveness (Aim 1), we will also use pre-clinical ovarian carcinoma models to determine the therapeutic effectiveness of adoptively transferred T cells lacking Foxp1 (Aim 2). Our initial experiments show that ovarian tumor-bearing mice receiving in vitro-primed anti-tumor T cells deficient in Foxp1 have superior survival over control mice, providing a rationale for novel therapeutic interventions targeting Foxp1 in tumor-reactive T cells from ovarian cancer-bearing women.
In summary, our proposed work will have a profound effect on the field by defining a novel mechanism for the loss-of-function of anti-tumor T cells in ovarian cancer, which may be applicable to other lethal epithelial tumors. The accomplishment of the work will provide both a mechanistic rationale and proof-of-concept for new interventions aimed at maximizing the effectiveness of adoptively transferred tumor-reactive T cells. Our long-term goal is to develop improved treatment options for ovarian cancer in clinic through adoptive transfer of tumor-reactive T cells, which are genetically modified to overcome tumor-induced immune suppression.
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Hui Hu, Ph.D.
Department of Microbiology
University of Alabama at Birmingham
Bevill Biomedical Sciences Research Building
845 19th Street South
Birmingham AL 35294-2170