An engineered viral protein rewires signaling pathways to overcome T cell suppression.

Abstract

Cancer can evade destruction by depriving T cells of cytokines, such as IL-2, that cause JAK-STAT signaling required for T cell functionality. We hypothesized that the direct activation of STAT proteins in a cytokine-independent manner could restore the signals needed by T cells. Because STATs are regulated by phosphorylation, we predicted that enforced recruitment of kinase activity to STATs could activate them directly in the absence of cytokine. Tyrosine-protein kinase-interacting protein (TIP), expressed by Herpesvirus saimiri, co-opts LCK kinase by recruiting LCK to non-canonical substrates, including STATs. We evaluated whether a minimal region of TIP could be isolated from the full-length viral protein and combined with STAT binding sites derived from cytokine receptors. Using this platform, we demonstrate that LCK kinase activity can be recruited to targeted STAT proteins to activate them. We determined that a STAT5 activator (aSTAT5) allowed CD8+ T cells to remain viable in the absence of IL-2 and retained their capacity to produce IFNg and kill cancer cells ex vivo. We therefore incorporated aSTAT5 into tumor-specific T cells (TST) and transferred them into tumor-bearing mice. We determined that aSTAT5 TST caused potent tumor regression and reduced tumor outgrowth due to improved T cell persistence and functionality. Our findings highlight that T cells can be improved to resist the miscommunication that cancer causes by targeting intracellular signaling pathways.