IRF4 overexpression in therapeutic anti-tumor CD8 T cells inhibits tumor growth by driving functional state transition of therapeutic and endogenous CD8 T cells in tumors

Abstract

Abstract Objective We discovered that IRF4 inhibits CD4 T cell dysfunction after transplantation (Immunity 47:1114). Here we study the role of IRF4 in regulating anti-tumor CD8 T cell response. Methods In model 1, different tumor cell lines were injected s.c. into mice with T cell-specific IRF4 deletion or control mice. In model 2, B16F10 melanoma-reactive Pmel-1 CD8 T cells were transduced with IRF4-GFP or GFP-control, and injected i.v. into congenic mice at 3 days post-s.c. injection of B16F10 cells. On day 14, T cell states in tumors were defined by single cell RNA-seq and flow cytometric analyses. Results IRF4 deletion in T cells significantly accelerated the progression of syngeneic TRAMP-C1 prostate cancer and B16F10 melanoma, and even enabled the growth of allogeneic CT26 Balb/c tumors. Adoptive transfer of IRF4-GFP transduced Pmel-1 T cells was significantly more potent than GFP-control transuded Pmel-1 cells in inhibiting B16F10 melanoma growth. In the GFP-control cell-transfer group, most Pmel-1 and endogenous CD8 T cells in tumors remained naïve-like or transitory states (expressed TCF1 but not effector molecules). In the IRF4-GFP cell-transfer group, more than half of Pmel-1 and endogenous CD8 T cells in tumors successfully developed into effector T cells that expressed multiple effector molecules. Conclusions IRF4 in T cells governs anti-tumor immunity. IRF4 overexpression in therapeutic T cells improves their anti-tumor potency.