title: IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.
abstract: 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.
authors.affiliation: University of Maryland Medical Center, Baltimore, MD 21201, United States.
authors.forename: Elise K
authors.initials: EK
authors.lastname: Heon
authors.affiliation: Department of Plastic and Reconstructive Surgery, PLA General Hospital, Beijing, 100853, China.
authors.forename: Hasi
authors.initials: H
authors.lastname: Wulan
authors.affiliation: Brown University, Providence, RI 02912, United States.
authors.forename: Loch P
authors.initials: LP
authors.lastname: Macdonald
authors.affiliation: Brown University, Providence, RI 02912, United States.
authors.forename: Adel O
authors.initials: AO
authors.lastname: Malek
authors.affiliation: Brown University, Providence, RI 02912, United States.
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Braunstein
authors.affiliation: Brown University, Providence, RI 02912, United States.
authors.forename: Connie G
authors.initials: CG
authors.lastname: Eaves
authors.affiliation: Brown University, Providence, RI 02912, United States.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Schattner
authors.affiliation: University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Allen
authors.affiliation: University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Alexander
authors.affiliation: University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Hawkins
authors.affiliation: University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Dermot W
authors.initials: DW
authors.lastname: McGovern
authors.affiliation: University of Wisconsin, Madison, WI 53706, United States.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Freeman
authors.affiliation: University of Illinois, Chicago, IL 60607, United States.
authors.forename: Eitan P
authors.initials: EP
authors.lastname: Amir
authors.affiliation: University of Illinois, Chicago, IL 60607, United States.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huse
authors.affiliation: University of Texas, Austin, TX 78712, United States.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Zaltzman
authors.affiliation: University of Texas, Austin, TX 78712, United States.
authors.forename: Noah P
authors.initials: NP
authors.lastname: Kauff
authors.affiliation: University of Texas, Austin, TX 78712, United States.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Meyers
authors.affiliation: University of Texas, Austin, TX 78712, United States. Electronic address: GleasonM@cblabs.org.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Gleason
authors.affiliation: University of Texas, Austin, TX 78712, United States. Electronic address: OverholtzerM@cblabs.org.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Overholtzer
authors.affiliation: Ohio State University, Columbus, OH 43210, United States.
authors.forename: Sam S
authors.initials: SS
authors.lastname: Wiseman
authors.affiliation: Ohio State University, Columbus, OH 43210, United States.
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Streutker
authors.affiliation: Ohio State University, Columbus, OH 43210, United States.
authors.forename: Sylvia W
authors.initials: SW
authors.lastname: Asa
authors.affiliation: Ohio State University, Columbus, OH 43210, United States.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: McAlindon
authors.affiliation: University of Illinois, Chicago, IL 60607, United States. Electronic address: Polly.Newcomb@mcgene.org.
authors.forename: Polly O
authors.initials: PO
authors.lastname: Newcomb
authors.affiliation: University of Illinois, Chicago, IL 60607, United States. Electronic address: Poul.Sorensen@mcgene.org.
authors.forename: Poul M
authors.initials: PM
authors.lastname: Sorensen
authors.affiliation: University of Illinois, Chicago, IL 60607, United States. Electronic address: Oliver.Press@mcgene.org.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Press
mesh_terms: D000368:Aged; D000906:Antibodies / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D037161:Galectins / Q000494:pharmacology; D015870:Gene Expression; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009367:Neoplasm Staging; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C508609:IL10 protein, human; C569274:IL15 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; C105032:LGALS9 protein, human; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: Breast cancer; IL-15; Tim-3; Tumor-infiltrating CD8(+) T cell