Ex vivo conditioning with IL-12 protects tumor-infiltrating CD8+ T cells from negative regulation by local IFN-?.

ABSTRACT: 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-?. In this report, we further elucidate the mechanism of this potency, showing that IL-12 additionally counteracts the negative regulatory effects of autocrine IFN-?. IL-12 not only downregulates PD-1 expression by T cells, thus minimizing the effects of IFN-?-induced PD-L1 upregulation by tumor stromal cells, but also inhibits IFN?R2 expression, thereby protecting T cells from IFN-?-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-?, but also to the additional capacity of IL-12 to counter the negative regulatory effects of autocrine IFN-?.

SUBMITTER: Lin L 

PROVIDER: S-EPMC6428620 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature