PMID- 34016722
OWN - NLM
STAT- MEDLINE
DCOM- 20220105
LR  - 20240226
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 9
IP  - 5
DP  - 2021 May
TI  - Modulation of lactate-lysosome axis in dendritic cells by clotrimazole 
      potentiates antitumor immunity.
LID - 10.1136/jitc-2020-002155 [doi]
LID - e002155
AB  - BACKGROUND: Dendritic cells (DCs) play a critical role in antitumor immunity, but 
      the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to 
      unsustainable DC function in tumor antigen presentation. Thus, identifying drugs 
      that could enhance DC-based antitumor immunity and uncovering the underlying 
      mechanism may provide new therapeutic options for cancer immunotherapy. METHODS: 
      In vitro antigen presentation assay was used for DC-modulating drug screening. 
      The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. 
      B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and Batf3(-/-) mice were 
      used to analyze the in vivo therapy efficacy and impact on tumor immune 
      microenvironment by clotrimazole treatment. RESULTS: By screening a group of 
      small molecule inhibitors and the US Food and Drug Administration (FDA)-approved 
      drugs, we identified that clotrimazole, an antifungal drug, could promote 
      DC-mediated antigen presentation and enhance T cell response. Mechanistically, 
      clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and 
      enhanced the lysosome pathway and Chop expression in DCs subsequently induced DC 
      maturation and T cell activation. Importantly, in vivo clotrimazole 
      administration induced intratumor immune infiltration and inhibited tumor growth 
      depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of 
      anti-PD1 antibody. CONCLUSIONS: Our findings showed that clotrimazole could 
      trigger DC activation via the lactate-lysosome axis to promote antigen 
      cross-presentation and could be used as a potential combination therapy approach 
      to improving the therapeutic efficacy of anti-PD1 immunotherapy.
CI  - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Wang, Zining
AU  - Wang Z
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China 
      xiaxj@sysucc.org.cn wangzn@sysucc.org.cn.
FAU - Xu, Feifei
AU  - Xu F
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Hu, Jie
AU  - Hu J
AD  - Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen 
      University, Guangzhou, China.
FAU - Zhang, Hongxia
AU  - Zhang H
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Cui, Lei
AU  - Cui L
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Lu, Wenhua
AU  - Lu W
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - He, Wenzhuo
AU  - He W
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
AD  - Department of The VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, 
      China.
FAU - Wang, Xiaojuan
AU  - Wang X
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Li, Mengyun
AU  - Li M
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Zhang, Huanling
AU  - Zhang H
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Xiong, Wenjing
AU  - Xiong W
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Xie, Chunyuan
AU  - Xie C
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Liu, Yongxiang
AU  - Liu Y
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Zhou, Penghui
AU  - Zhou P
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
FAU - Liu, Jinyun
AU  - Liu J
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
AD  - Metabolic Innovation Center, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, China.
FAU - Huang, Peng
AU  - Huang P
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
AD  - Metabolic Innovation Center, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, China.
FAU - Qin, Xiaofeng Frank
AU  - Qin XF
AD  - Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy 
      of Medical Sciences and Peking Union Medical College, Beijing, China.
AD  - Suzhou Institute of Systems Medicine, Suzhou, China.
FAU - Xia, Xiaojun
AU  - Xia X
AUID- ORCID: 0000-0003-4444-7472
AD  - State Key Laboratory of Oncology in South China, Collaborative Innovation Center 
      for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China 
      xiaxj@sysucc.org.cn wangzn@sysucc.org.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Basic-Leucine Zipper Transcription Factors)
RN  - 0 (Ddit3 protein, mouse)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Immunomodulating Agents)
RN  - 0 (Pdcd1 protein, mouse)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Repressor Proteins)
RN  - 0 (SNFT protein, mouse)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 33X04XA5AT (Lactic Acid)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - EC 2.7.1.1 (hexokinase 2, mouse)
RN  - G07GZ97H65 (Clotrimazole)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Basic-Leucine Zipper Transcription Factors/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Clotrimazole/*pharmacology
MH  - Colonic Neoplasms/*drug therapy/genetics/immunology/metabolism
MH  - Dendritic Cells/*drug effects/immunology/metabolism
MH  - Female
MH  - Hexokinase/metabolism
MH  - Immune Checkpoint Inhibitors/pharmacology
MH  - Immunomodulating Agents/*pharmacology
MH  - Lactic Acid/*metabolism
MH  - Lymphocyte Activation/drug effects
MH  - Lymphocytes, Tumor-Infiltrating/drug effects/immunology/metabolism
MH  - Lysosomes/*drug effects/immunology/metabolism
MH  - Melanoma, Experimental/*drug therapy/genetics/immunology/metabolism
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Nude
MH  - Programmed Cell Death 1 Receptor/antagonists & inhibitors/metabolism
MH  - Repressor Proteins/genetics/metabolism
MH  - Skin Neoplasms/*drug therapy/genetics/immunology/metabolism
MH  - T-Lymphocytes/drug effects/immunology/metabolism
MH  - Transcription Factor CHOP/metabolism
MH  - Tumor Burden
MH  - Tumor Microenvironment
MH  - Mice
PMC - PMC8141455
OTO - NOTNLM
OT  - dendritic cells
OT  - immunotherapy
COIS- Competing interests: No, there are no competing interests.
EDAT- 2021/05/22 06:00
MHDA- 2022/01/06 06:00
PMCR- 2021/05/20
CRDT- 2021/05/21 06:01
PHST- 2021/04/05 00:00 [accepted]
PHST- 2021/05/21 06:01 [entrez]
PHST- 2021/05/22 06:00 [pubmed]
PHST- 2022/01/06 06:00 [medline]
PHST- 2021/05/20 00:00 [pmc-release]
AID - jitc-2020-002155 [pii]
AID - 10.1136/jitc-2020-002155 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2021 May;9(5):e002155. doi: 10.1136/jitc-2020-002155.