IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.

Autor: Heon EK; University of Maryland Medical Center, Baltimore, MD 21201, United States., Wulan H; Department of Plastic and Reconstructive Surgery, PLA General Hospital, Beijing, 100853, China., Macdonald LP; Brown University, Providence, RI 02912, United States., Malek AO; Brown University, Providence, RI 02912, United States., Braunstein GH; Brown University, Providence, RI 02912, United States., Eaves CG; Brown University, Providence, RI 02912, United States., Schattner MD; Brown University, Providence, RI 02912, United States., Allen PM; University of Wisconsin, Madison, WI 53706, United States., Alexander MO; University of Wisconsin, Madison, WI 53706, United States., Hawkins CA; University of Wisconsin, Madison, WI 53706, United States., McGovern DW; University of Wisconsin, Madison, WI 53706, United States., Freeman RL; University of Wisconsin, Madison, WI 53706, United States., Amir EP; University of Illinois, Chicago, IL 60607, United States., Huse JD; University of Illinois, Chicago, IL 60607, United States., Zaltzman JS; University of Texas, Austin, TX 78712, United States., Kauff NP; University of Texas, Austin, TX 78712, United States., Meyers PG; University of Texas, Austin, TX 78712, United States., Gleason MH; University of Texas, Austin, TX 78712, United States. Electronic address: GleasonM@cblabs.org., Overholtzer MG; University of Texas, Austin, TX 78712, United States. Electronic address: OverholtzerM@cblabs.org., Wiseman SS; Ohio State University, Columbus, OH 43210, United States., Streutker CD; Ohio State University, Columbus, OH 43210, United States., Asa SW; Ohio State University, Columbus, OH 43210, United States., McAlindon TP; Ohio State University, Columbus, OH 43210, United States., Newcomb PO; University of Illinois, Chicago, IL 60607, United States. Electronic address: Polly.Newcomb@mcgene.org., Sorensen PM; University of Illinois, Chicago, IL 60607, United States. Electronic address: Poul.Sorensen@mcgene.org., Press OA; University of Illinois, Chicago, IL 60607, United States. Electronic address: Oliver.Press@mcgene.org.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2015 Aug 14; Vol. 464 (1), pp. 360-6. Date of Electronic Publication: 2015 Jun 30.
DOI: 10.1016/j.bbrc.2015.06.162
Abstrakt: IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy.
(Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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