Eileen M. Higham, Biological Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Ave., E17-132, Cambridge, MA 02139, K. Dane Wittrup, Chemical Engineering, Biological Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Ave., E19-551, Cambridge, MA 02139, and Jianzhu Chen, Biology and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Ave., E17-131, Cambridge, MA 02139.
Prostate cancer is the most prevalent malignancy among American men, leading to significant mortality each year. This is in part due to a lack of effective treatments for advanced prostate cancer, highlighting the critical need for novel therapies to treat this disease. The prostate is considered an ideal organ for cancer immunotherapy, because of its non-essential nature, and because of the presence of several prostate-specific antigens that could serve as targets for an immune response. However, such therapy is limited by tolerization of CD8+ T cells in the tumor local environment, essentially abrogating an anti-tumor response. The objective of this work is to understand the interactions between CD8+ T cells and tumor cells that lead to tolerance, and to design therapies to reinvigorate the immune response. A spontaneous prostate cancer model, the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model (1), has been used to develop an in vivo system to explore tolerance. Tumor-induced tolerance has been characterized using TRAMP mice engineered to express the antigen SIY in their prostate tissue, TRAMP-SIY mice, coupled with T cells that recognize Kb-SIY, 2C T cells. We have demonstrated that 2C T cells are tolerized in the tumor local environment of TRAMP-SIY mice through both their inability to produce IFN-γ and their impaired cytotoxic killing functions. In vivo screens have also been used to define critical mechanisms of tolerance in this model, most notably tolerance mediated by cross-presentation. We have shown that systemic α-CD40 administration can initially overcome tolerizing mechanisms in TRAMP-SIY mice and can restore function to 2C T cells. Based on these findings, novel localized α-CD40 therapies are being rationally designed to break tolerance, while minimizing the autoimmune complications observed with systemic treatments.
1. Greenberg, N.,; DeMayo, F.; Finegold, M.; Medina, D.; Tilley, W.; Aspinall, J.; Cunha, G.; Donjacour, A.; Matusik, R.; Rosen, J.; Proc. Natl. Acad. Sci., 92, 3439-3443, 1995.