Lin et al. studied the mechanism of improved antitumor efficacy of IL-12-pretreated, adoptively transferred (ADT) CD8+ T cells. IL-12 exposure before ADT of Pmel-transgenic CD8+ T cells enhanced persistence and IFNγ production within the B16F10 TME and dampened PD-1 and IFNγR2 expression. In human melanoma CD8+ TILs, IL-12 treatment in vitro reduced PD-1 and enhanced IFNγ levels. Pmel IFNγR1-/- CD8+ T cells, lacking IFNγ signaling, showed improved expansion, reduced apoptosis, and enhanced survival, suggesting that IL-12 suppression of the IFNγ receptor reduces responsiveness to IFNγ and its downstream negative regulatory effects.

Optimal ex vivo expansion protocols for adoptive cell therapy (ACT) must yield T cells able to effectively home to tumors and survive the inhospitable conditions of the tumor microenvironment (TME), while simultaneously exerting persistent anti-tumor effector functions. Our previous work has shown that ex vivo activation in the presence of IL-12 can induce optimal expansion of murine CD8(+) T cells, thus resulting in significant tumor regression after ACT mostly via sustained secretion of IFN-gamma. In this report, we further elucidate the mechanism of this potency, showing that IL-12 additionally counteracts the negative regulatory effects of autocrine IFN-gamma. IL-12 not only downregulates PD-1 expression by T cells, thus minimizing the effects of IFN-gamma-induced PD-L1 upregulation by tumor stromal cells, but also inhibits IFNgammaR2 expression, thereby protecting T cells from IFN-gamma-induced cell death. Thus, the enhanced anti-tumor activity of CD8(+) T cells expanded ex vivo in the presence of IL-12 is due not only to the ability of IL-12-stimulated cells to secrete sustained levels of IFN-gamma, but also to the additional capacity of IL-12 to counter the negative regulatory effects of autocrine IFN-gamma.

Author Info: (1) Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA. (2) Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid

Author Info: (1) Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA. (2) Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue NE40, Cleveland, OH, 44195, USA. (3) Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue NE40, Cleveland, OH, 44195, USA. (4) Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue NE40, Cleveland, OH, 44195, USA. (5) Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue NE40, Cleveland, OH, 44195, USA. (6) Department of Hematology and Medical Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA. (7) Department of Pathology, Cleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland, OH, USA. (8) Department of Plastic Surgery, Dermatology and Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, USA. (9) Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue NE40, Cleveland, OH, 44195, USA. (10) Department of Hematology and Medical Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA. (11) Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue NE40, Cleveland, OH, 44195, USA. diazc2@ccf.org.

Less