Efficient T cell adoptive transfer in lymphoreplete hosts mediated by transient activation of Stat5 signaling

Abstract

Lymphodepleting pre-conditioning is a nearly universal component of Tcell adoptive transfer protocols. The side effects of pre-conditioning regimens used in adoptive cell therapy are clinically significant and include pan-cytopenia, immune suppression, and reactive myelopoiesis. We conducted studies to test the hypothesis that the mechanisms underlying effective engraftment are cell autonomous and not dependent on a lymphodepleted host immune status. These studies leveraged mouse models to examine the role of Stat5 signaling during Tcell adoptive transfer. We observed that, by transiently expressing a constitutively active mutamer of Stat5b during the process of adoptive transfer, we could completely obviate the need for lymphodepletion prior to adoptive transfer. Using several functional assays, we benchmark the function of the engrafted Tcells against Tcells transferred after conventional lymphodepletion. These studies identify a cell-autonomous mechanism driven by transient Stat5b signaling with lasting effects on Tcell phenotype and function. Furthermore, the results presented suggest that adoptive Tcell therapy could be improved by removing lymphodepletion protocols entirely and replacing them with RNA transfection of Tcells with transcripts encoding active Stat5.