PMID- 31914650
OWN - NLM
STAT- MEDLINE
DCOM- 20200706
LR  - 20201019
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 34
IP  - 1
DP  - 2020 Jan
TI  - IL-18R-dependent and independent pathways account for IL-18-enhanced antitumor 
      ability of CAR-T cells.
PG  - 1768-1782
LID - 10.1096/fj.201901809R [doi]
AB  - Interleukin-18 (IL-18) has been demonstrated to augment the antitumor capacity of 
      chimeric antigen receptor-T cells (CAR-T) but the underlying mechanisms are 
      largely unknown. Here we explored the effects and mechanisms of exogenous IL-18 
      on the antitumor response of CAR-T cells. IL-18 boosted the cytotoxicity of human 
      epidermal growth factor receptor-2 (HER2)-specific CAR-T cells ex vivo and 
      enhanced the antitumor efficacy of the CAR-T cells in immunodeficient mice, 
      moreover, IL-18 improved the antitumor capacity of OVA-specific T cells in 
      immunocompetent mice, indicating the universal enhancing function of IL-18 for 
      adoptive cell therapy. To address the roles of IL-18 receptor (IL-18R) in the 
      enhancing function, we evaluated the effects of IL-18R knockout (IL-18R(-/-)) 
      condition in immunocompetent host and CAR-T cells on the IL-18-enhanced antitumor 
      activities. Interestingly, IL-18 persisted to improve the antitumor ability of 
      IL-18R intact CAR-T cells in IL-18R(-/-) mice. For IL-18R(-/-) CAR-T cells, 
      however, IL-18 still holds the enhancing ability to boost the antitumor efficacy 
      in IL-18R(-/-) mice, albeit the ex vivo tumor-killing ability was lower than that 
      of IL-18R intact CAR-T cells, indicating that IL-18R-independent pathway is 
      involved in the enhancement. Furthermore, tagged IL-18 binded to the membrane of 
      IL-18R(-/-) splenic and lymph node cells and IL-18R intact and IL-18R(-/-) CAR-T 
      cells showed distinct transcriptomic profiles when stimulated by IL-18. These 
      data demonstrate that IL-18R-independent pathways contribute to functions of 
      IL-18.
CI  - (c) 2019 Federation of American Societies for Experimental Biology.
FAU - Huang, Yong
AU  - Huang Y
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Li, Dan
AU  - Li D
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Zhang, Peng-Fei
AU  - Zhang PF
AD  - Department of Medical Oncology, Cancer Center, West China Hospital, West China 
      Medical School, Sichuan University and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Liu, Mei
AU  - Liu M
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Liang, Xiao
AU  - Liang X
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
AD  - Department of Medical Oncology, Cancer Center, West China Hospital, West China 
      Medical School, Sichuan University and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Yang, Xiao
AU  - Yang X
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Jiang, Lin
AU  - Jiang L
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Zhang, Li-Feng
AU  - Zhang LF
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
AD  - Department of Neurosugery, West China Hospital, Sichuan University, Chengdu, 
      China.
FAU - Zhou, Wei-Lin
AU  - Zhou WL
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Su, Jin-Hua
AU  - Su JH
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Gong, You-Ling
AU  - Gong YL
AD  - Department of Thoracic Oncology, State Key Laboratory of Biotherapy, Cancer 
      Center, West China Hospital, Sichuan University, Chengdu, China.
FAU - Gou, Hong-Feng
AU  - Gou HF
AD  - Department of Medical Oncology, Cancer Center, West China Hospital, West China 
      Medical School, Sichuan University and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
FAU - Wei, Yu-Quan
AU  - Wei YQ
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
AD  - Department of Medical Oncology, Cancer Center, West China Hospital, West China 
      Medical School, Sichuan University and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
AD  - Department of Thoracic Oncology, State Key Laboratory of Biotherapy, Cancer 
      Center, West China Hospital, Sichuan University, Chengdu, China.
FAU - Wang, Wei
AU  - Wang W
AD  - Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, 
      West China Hospital, Sichuan University, and Collaborative Innovation Center for 
      Biotherapy, Chengdu, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191206
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Antineoplastic Agents)
RN  - 0 (IL18 protein, human)
RN  - 0 (Interleukin-18)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Receptors, Interleukin-18)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*metabolism
MH  - Cell Line
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Immunotherapy, Adoptive/methods
MH  - Interleukin-18/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Receptors, Antigen, T-Cell/*metabolism
MH  - Receptors, Interleukin-18/*metabolism
MH  - Signal Transduction/*physiology
MH  - T-Lymphocytes/*metabolism
MH  - Xenograft Model Antitumor Assays/methods
OTO - NOTNLM
OT  - CAR-T
OT  - IL-18
OT  - IL-18 receptor
OT  - cancer immunotherapy
EDAT- 2020/01/10 06:00
MHDA- 2020/07/07 06:00
CRDT- 2020/01/10 06:00
PHST- 2019/07/18 00:00 [received]
PHST- 2019/10/03 00:00 [revised]
PHST- 2019/10/09 00:00 [accepted]
PHST- 2020/01/10 06:00 [entrez]
PHST- 2020/01/10 06:00 [pubmed]
PHST- 2020/07/07 06:00 [medline]
AID - 10.1096/fj.201901809R [doi]
PST - ppublish
SO  - FASEB J. 2020 Jan;34(1):1768-1782. doi: 10.1096/fj.201901809R. Epub 2019 Dec 6.