Studying the antagonistic relationship between NKG2D and TGF-β in CD8+ T cells (IRM14P.449)

Abstract

Abstract One of the major hurdles in cancer vaccine and adoptive T cell transfer therapy (ACT) development is diminished effectiveness and persistence of T lymphocytes due to immuno-suppressive factors. TGF-β is highly prevalent immuno-suppressive factor secreted by tumor which negatively regulates persistence and functionality of CD8+ T cells. Natural killer group 2, member D (NKG2D) is a stimulatory receptor majorly expressed on the surface of NK and CD8+ T cells. Others including our lab have shown that NKG2D activation on CD8+ T cells enhances their function, proliferation and persistence. Accordingly, we hypothesized that NKG2D signaling reverses the inhibitory effects of TGF-β on CD8+ T cells. We found that in vitro NKG2D activation prevented TGF-β mediated inhibition of proliferation and granzyme B expression in human CD8+ T cells. Interestingly, we also found that TGF-β down regulates the surface expression of NKG2D in human and mouse CD8+ T cells. In the presented research we will test two alternative hypotheses to elucidate molecular mechanism underlying NKG2D and TGF-β’s antagonistic effects. NKG2D opposes TGF-β’s suppressive effects in CD8+ T cells by i) repressing levels of transcription factor T-bet ii) increasing levels of inhibitor of TGF-β signaling-regulator of G-protein signaling 3 (RGS3). The findings from this research will form basis to develop a therapeutic strategy to reverse TGF-β’s immunosuppressive effects in vivo that results in better anti-tumor immunity.