Engineering Robust T-Cell Response Against Immunosuppressive Tumors
- Author(s): Lorenzini, Michael Hideo
- Advisor(s): Wong, Gerard C. L.
- et al.
With the establishment of clinically effective adoptive T-cell therapy for metastatic cancer, efforts are growing to advance T-cell therapy for new indications, especially solid tumors. A major challenge, however, is that the antitumor activity of infused T cells can be suppressed by the cytokine transforming growth factor beta (TGFβ). To counteract TGFβ-mediated immunosuppression, a TGFβ-specific chimeric antigen receptor (TGFβ-CAR) was engineered and characterized in vitro. The TGFβ-CAR converted TGFβ from a suppressive signal to a stimulatory signal, enabling CD4+ and CD8+ T cells to overcome TGFβ-mediated dysfunction by blocking endogenous TGFβ signaling and triggering TGFβ-specific T-cell activation, Th1 cytokine production, and robust proliferation. These properties suggest the TGFβ-CAR could be incorporated into tumor-reactive T cells to boost antitumor activity. Alternatively, the TGFβ-CAR could be a tool for robust T-cell expansion ex vivo. To our knowledge, this is the first CAR specifically designed to respond to a soluble antigen.