Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect

被引:189
作者
Felices, Martin [1 ]
Lenvik, Alexander J. [1 ]
McElmurry, Ron [2 ]
Chu, Sami [1 ]
Hinderlie, Peter [1 ]
Bendzick, Laura [3 ]
Geller, Melissa A. [3 ]
Tolar, Jakub [2 ]
Blazar, Bruce R. [2 ]
Miller, Jeffrey S. [1 ]
机构
[1] Univ Minnesota, Div Hematol Oncol & Transplantat, Dept Med, Minneapolis, MN USA
[2] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Div Gynecol Oncol, Dept Obstet Gynecol & Womens Hlth, Minneapolis, MN USA
来源
JCI INSIGHT | 2018年 / 3卷 / 03期
关键词
NATURAL-KILLER-CELLS; ADOPTIVE TRANSFER; DOWN-REGULATION; T-CELLS; CANCER; CYTOKINE; CIS; ACTIVATION; PROMOTES; MEMORY;
D O I
10.1172/jci.insight.96219
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
NK cell-based immunotherapies have been gaining traction in the clinic for treatment of cancer. IL-15 is currently being used in number of clinical trials to improve NK cell expansion and function. The objective of this study is to evaluate the effect of repetitive IL-15 exposure on NK cells. An in vitro model in which human NK cells are continuously (on on on) or intermittently (on off on) treated with IL-15 was used to explore this question. After treatment, cells were evaluated for proliferation, survival, cell cycle gene expression, function, and metabolic processes. Our data indicate that continuous treatment of NK cells with IL-15 resulted in decreased viability and a cell cycle arrest gene expression pattern. This was associated with diminished signaling, decreased function both in vitro and in vivo, and reduced tumor control. NK cells continuously treated with IL-15 also displayed a reduced mitochondrial respiration profile when compared with NK cells treated intermittently with IL-15. This profile was characterized by a decrease in the spare respiratory capacity that was dependent on fatty acid oxidation (FAO). Limiting the strength of IL-15 signaling via utilization of an mTOR inhibitor rescued NK cell functionality in the group continuously treated with IL-15. The findings presented here show that human NK cells continuously treated with IL-15 undergo a process consistent with exhaustion that is accompanied by a reduction in FAO. These findings should inform IL-15-dosing strategies in NK cell cancer immunotherapeutic settings.
引用
收藏
页数:14
相关论文
共 40 条
[1]   CIS associates with the interleukin-2 receptor β chain and inhibits interleukin-2-dependent signaling [J].
Aman, MJ ;
Migone, TS ;
Sasaki, A ;
Ascherman, DP ;
Zhu, MH ;
Soldaini, E ;
Imada, K ;
Miyajima, A ;
Yoshimura, A ;
Leonard, WJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (42) :30266-30272
[2]  
Bachanova Veronika, 2014, Critical Reviews in Oncogenesis, V19, P133
[3]   T cell metabolism drives immunity [J].
Buck, Michael D. ;
O'Sullivan, David ;
Pearce, Erika L. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2015, 212 (09) :1345-1360
[4]   Redistribution, Hyperproliferation, Activation of Natural Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of Recombinant Human Interleukin-15 in Patients With Cancer [J].
Conlon, Kevin C. ;
Lugli, Enrico ;
Welles, Hugh C. ;
Rosenberg, Steven A. ;
Fojo, Antonio Tito ;
Morris, John C. ;
Fleisher, Thomas A. ;
Dubois, Sigrid P. ;
Perera, Liyanage P. ;
Stewart, Donn M. ;
Goldman, Carolyn K. ;
Bryant, Bonita R. ;
Decker, Jean M. ;
Chen, Jing ;
Worthy, Tat'Yana A. ;
Figg, William D., Sr. ;
Peer, Cody J. ;
Sneller, Michael C. ;
Lane, H. Clifford ;
Yovandich, Jason L. ;
Creekmore, Stephen P. ;
Roederer, Mario ;
Waldmann, Thomas A. .
JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (01) :74-U123
[5]   Natural Killer Cell Adoptive Transfer Therapy Exploiting the First Line of Defense Against Cancer [J].
Davis, Zachary B. ;
Felices, Martin ;
Verneris, Michael R. ;
Miller, Jeffrey S. .
CANCER JOURNAL, 2015, 21 (06) :486-491
[6]   Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth [J].
DeBerardinis, Ralph J. ;
Lum, Julian J. ;
Thompson, Craig B. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (49) :37372-37380
[7]   CIS is a potent checkpoint in NK cell-mediated tumor immunity [J].
Delconte, Rebecca B. ;
Kolesnik, Tatiana B. ;
Dagley, Laura F. ;
Rautela, Jai ;
Shi, Wei ;
Putz, Eva M. ;
Stannard, Kimberley ;
Zhang, Jian-Guo ;
Teh, Charis ;
Firth, Matt ;
Ushiki, Takashi ;
Andoniou, Christopher E. ;
Degli-Esposti, Mariapia A. ;
Sharp, Phillip P. ;
Sanvitale, Caroline E. ;
Infusini, Giuseppe ;
Liau, Nicholas P. D. ;
Linossi, Edmond M. ;
Burns, Christopher J. ;
Carotta, Sebastian ;
Gray, Daniel H. D. ;
Seillet, Cyril ;
Hutchinson, Dana S. ;
Belz, Gabrielle T. ;
Webb, Andrew I. ;
Alexander, Warren S. ;
Li, Shawn S. ;
Bullock, Alex N. ;
Babon, Jeffery J. ;
Smyth, Mark J. ;
Nicholson, Sandra E. ;
Huntington, Nicholas D. .
NATURE IMMUNOLOGY, 2016, 17 (07) :816-+
[8]   mTORC1-Dependent Metabolic Reprogramming Is a Prerequisite for NK Cell Effector Function [J].
Donnelly, Raymond P. ;
Loftus, Roisin M. ;
Keating, Sinead E. ;
Liou, Kevin T. ;
Biron, Christine A. ;
Gardiner, Clair M. ;
Finlay, David K. .
JOURNAL OF IMMUNOLOGY, 2014, 193 (09) :4477-4484
[9]   Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Rα complexes [J].
Elpek, Kutlu G. ;
Rubinstein, Mark P. ;
Bellemare-Pelletier, Angelique ;
Goldrath, Ananda W. ;
Turley, Shannon J. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (50) :21647-21652
[10]   Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells [J].
Fehniger, TA ;
Suzuki, K ;
Ponnappan, A ;
VanDeusen, JB ;
Cooper, MA ;
Florea, SM ;
Freud, AG ;
Robinson, ML ;
Durbin, J ;
Caligiuri, MA .
JOURNAL OF EXPERIMENTAL MEDICINE, 2001, 193 (02) :219-231