Direct activation of STAT5 to improve T cell therapeutics

About This Grant

PROJECT SUMMARY CD8+ T cells can kill cancerous cells, but they become disabled by a suppressive tumor microenvironment (TME) that is established by pancreatic ductal adenocarcinoma (PDAC) and other solid tumors that are refractory to current immunotherapies. The TME deprives CD8+ T cells of the cytokine-induced JAK-STAT signals they require to survive and remain functional. To overcome this critical barrier to a T cell-mediated anti-tumor response and prevent T cell dysfunction, specific cytokine-induced JAK-STAT signals must be restored. However, the development of cytokine receptor agonists has faced numerous challenges, including poor pharmacological properties and severe toxicities. We have pursued an alternative strategy and developed an activator of STAT5, the downstream mediator of IL-2 receptor signaling. Our preliminary data demonstrate that a STAT5 activator delivered by retroviral transduction to T cells ex vivo sustains CD8+ T cell viability and functionality under suppressive culture conditions where the pro-survival cytokine IL-2 is absent. Moreover, RNA sequencing revealed that a STAT5 activator promoted a memory-like T cell phenotype with reduced expression of genes associated with terminal effector differentiation and T cell exhaustion. Based on these preliminary findings, I will evaluate the hypothesis that a STAT5 activator can enhance the persistence and functionality of CD8+ T cells within the TME in vivo and can be used to expand memory-like CD8+ T cells ex vivo. In Aim 1, I will perform functional assays and gene expression analysis to compare CD8+ T cells cultured with cytokines to those where STAT5 is directly activated to determine how a STAT5 activator influences CD8+ T cell differentiation. I will also evaluate the translational potential of a STAT5 activator by testing its ability to promote human CD8+T cell survival and function ex vivo. In Aim 2, I will determine whether adoptively transferred tumor- specific T cells modified with a STAT5 activator can better sustain a T cell mediated anti-tumor response using a mouse model of PDAC. Tumor infiltrating T cells and the TME cell populations will be interrogated to address the mechanism that underlies an in vivo response. The experiments of these specific aims will address a fundamental barrier to the treatment of refractory solid tumors, such as PDAC, and provide me with robust foundational training in the field of cancer immunology.