An engineered viral peptide activates STAT proteins to promote CD8+ T cell functionality in the absence of IL-2 4041

Abstract Description T cell therapies have been developed that exploit the ability of CD8+ T cells to recognize and kill cancer cells. The efficacy of these therapies has been limited by the suppressive environment within solid tumors. The tumor deprives therapeutic T cells of the cytokine-induced JAK-STAT signals they need to survive and retain their functionality. We therefore engineered a peptide that recruits LCK, a non-JAK tyrosine kinase, to a targeted STAT to phosphorylate and activate it. Because the cytokine IL-2 activates STAT5 to sustain T cell survival, we hypothesized that a STAT5 activator (aSTAT5) could enable CD8+ T cells to function in the absence of IL-2. To test this hypothesis, we transduced primary CD8+ T cells to incorporate aSTAT5 and systematically evaluated readouts of T cell function ex vivo in the presence or absence of IL-2. We determined that aSTAT5 sustained CD8+ T cell viability and cytotoxicity against cancer cells, as well as their capacity to produce IFNγ. We further demonstrated that aSTAT5 rendered T cells resistant to JAK inhibition but were sensitized to LCK inhibition by PP2. These findings demonstrate a new strategy to activate STAT proteins in T cells for therapeutic applications. We have begun to incorporate aSTAT5 into pancreatic ductal adenocarcinoma cells (PDA) specific T cells that recognize the mesothelin tumor antigen to determine whether they can resist suppression to recognize and eliminate cancer cells within highly suppressive PDA tumors. Funding Sources NIGMS R35 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)