期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 68, 期 3, 页码 395-405出版社
SPRINGER
DOI: 10.1007/s00262-018-2280-3
关键词
Melanoma/skin cancers; Tumor promotion and progression; Models of host-tumor interactions; Tumor microenvironment; Adoptive T cells transfer; PD-1
资金
- National Cancer Institute [K01CA134927, R21CA188767]
- Velosano Pilot Research Award
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 IFN gamma R2 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.
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