NKG2D Signaling and Cd8+ T Cells Survival in the Hypoxic Tumor Microenvironment

Hypoxic regions within solid tumors are immunosuppressive, house cancer cells that are resistant to therapy, and are linked with poor prognosis. We hypothesize that stimulation of the NKG2D receptor during activation of CD8+ T cells promotes cell survival and overcomes hypoxia-induced suppression. The presence of NKG2D ligands, during activation, increased the percentage of live cells under both normoxic and hypoxic conditions. Furthermore, this treatment increased Bcl-2 protein levels under normoxia as well as hypoxia. STAT5, a known regulator of Bcl-2, was also activated to a greater extent with NKG2D receptor stimulation, and NKG2D deficient cells were unable to activate STAT5. In support of STAT5-mediated regulation of Bcl-2, cells with high levels of activated STAT5 also had elevated Bcl-2 protein levels. In conclusion, NKG2D stimulation during activation of CD8+ T cells promotes cell survival under hypoxia by STAT5-mediated upregulation of the anti-apoptotic protein, Bcl-2.