Abstract B113: Rewiring T cell signaling to activate STAT proteins in T cells that target pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an immunosuppressive tumor microenvironment (TME) that disrupts the instructive signals required for CD8+ T cells to kill cancer cells. Pro-survival cytokines, such as IL-2, are depleted, which abrogates the JAK1/3–STAT5 signaling required to maintain T cell survival and effector function. Consequently, inhibitory pathways dominate and promote T cell dysfunction. Restoration of this signaling axis is therefore an attractive therapeutic strategy. Although high-dose IL-2 was an early FDA-approved immunotherapy for the treatment of metastatic melanoma and renal cell carcinoma, its clinical efficacy was limited by severe systemic toxicity and modest response rates. Thus, there is a critical need to develop novel strategies to restore the STAT5 signals needed to maintain T cell survival and effector function in the TME without the drawbacks of systemic cytokine administration. We discovered that the herpesvirus saimiri tyrosine kinase–interacting protein (TIP) could be engineered to recruit the tyrosine kinase LCK to specific endogenous STAT proteins in T cells to induce their phosphorylation and activation in a cytokine-independent manner. Using this approach, we demonstrated that STAT5 activity potentiates T cell survival and effector function in mouse tumor models by preventing hallmarks of T cell exhaustion. Based on these findings, we predict that cytokine-independent activation of STAT5 could enhance the efficacy of T cell therapies by sustaining T cell function in PDAC tumors and reshaping STAT-dependent signaling pathways.The tumor antigen mesothelin (MSLN) is commonly upregulated in PDAC and is a leading target for CAR- and TCR-engineered T cell therapies. However, MSLN-directed CAR T cells have thus far demonstrated limited clinical efficacy. Our preliminary in vivo studies using a subcutaneous PDAC model combined with MSLN-specific T cells indicate that STAT5 activity results in tenfold greater T cell infiltration and reduced tumor outgrowth. Using this approach, we have evaluated additional STAT activation profiles that enhance or diminish T cell persistence within PDAC tumors. Our data demonstrate that STAT5 activation, either alone or in combination with other STAT proteins, enhances intratumoral T cell persistence. Elucidating how STAT activity reshapes T cell phenotype in PDAC will establish a framework for designing next-generation T cell therapies capable of functioning in cytokine-dysregulated solid tumors.