TGFβ Programs Central Memory Differentiation in <i>Ex Vivo</i> –Stimulated Human T Cells

Abstract

The adoptive transfer of <i>ex vivo</i>-expanded T cells is a promising approach to treat several malignancies. Several lines of evidence support that the infusion of T cells with early memory features, capable of expanding and persisting after transfer, are associated with better outcomes. We report herein that exposure to exogenous TGFβ during human T-cell stimulation <i>ex vivo</i> leads to the accumulation of early/central memory (Tcm) cells. Exposure to TGFβ suppressed the expression of BLIMP-1, a key orchestrator of effector T-cell differentiation, and led to the upregulation of the memory-associated transcription factor ID3. Accordingly, this was associated with an early memory transcriptional signature in both CD4⁺ and CD8⁺ T-cell subsets. The T cells stimulated in the presence of TGFβ expanded normally, and displayed polyfunctional features and no suppressive activity. The adoptive transfer of <i>ex vivo</i>-stimulated T cells into immunodeficient mice confirmed that TGFβ-conditioned cells had an enhanced capacity to persist and mediate xenogeneic graft-versus-host disease, as predicted by their early T-cell memory phenotype. Chimeric antigen receptor-expressing T cells generated in the presence of exogenous TGFβ were cytotoxic and more effective at controlling tumor growth in immunodeficient animals. This work unveils a new role for TGFβ in memory T-cell differentiation and indicates that TGFβ signaling may be harnessed to program Tcm differentiation in the context of <i>ex vivo</i> T-cell stimulation for adoptive immunotherapy in humans.