PMID- 32780726
OWN - NLM
STAT- MEDLINE
DCOM- 20210521
LR  - 20221106
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 5
IP  - 17
DP  - 2020 Sep 3
TI  - PPT1 inhibition enhances the antitumor activity of anti-PD-1 antibody in 
      melanoma.
LID - 133225 [pii]
LID - 10.1172/jci.insight.133225 [doi]
LID - e133225
AB  - New strategies are needed to enhance the efficacy of anti-programmed cell death 
      protein antibody (anti-PD-1 Ab) in cancer. Here, we report that inhibiting 
      palmitoyl-protein thioesterase 1 (PPT1), a target of chloroquine derivatives like 
      hydroxychloroquine (HCQ), enhances the antitumor efficacy of anti-PD-1 Ab in 
      melanoma. The combination resulted in tumor growth impairment and improved 
      survival in mouse models. Genetic suppression of core autophagy genes, but not 
      Ppt1, in cancer cells reduced priming and cytotoxic capacity of primed T cells. 
      Exposure of antigen-primed T cells to macrophage-conditioned medium derived from 
      macrophages treated with PPT1 inhibitors enhanced melanoma-specific killing. 
      Genetic or chemical Ppt1 inhibition resulted in M2 to M1 phenotype switching in 
      macrophages. The combination was associated with a reduction in myeloid-derived 
      suppressor cells in the tumor. Ppt1 inhibition by HCQ, or DC661, induced cyclic 
      GMP-AMP synthase/stimulator of interferon genes/TANK binding kinase 1 pathway 
      activation and the secretion of interferon-beta in macrophages, the latter being a 
      key component for augmented T cell-mediated cytotoxicity. Genetic Ppt1 inhibition 
      produced similar findings. These data provide the rationale for this combination 
      in melanoma clinical trials and further investigation in other cancers.
FAU - Sharma, Gaurav
AU  - Sharma G
AD  - Abramson Cancer Center and Department of Medicine.
FAU - Ojha, Rani
AU  - Ojha R
AD  - Abramson Cancer Center and Department of Medicine.
FAU - Noguera-Ortega, Estela
AU  - Noguera-Ortega E
AD  - Abramson Cancer Center and Department of Medicine.
FAU - Rebecca, Vito W
AU  - Rebecca VW
AD  - Abramson Cancer Center and Department of Medicine.
FAU - Attanasio, John
AU  - Attanasio J
AD  - Department of Systems Pharmacology and Translational Therapeutics and Penn 
      Institute for Immunology, and.
FAU - Liu, Shujing
AU  - Liu S
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Piao, Shengfu
AU  - Piao S
AD  - Abramson Cancer Center and Department of Medicine.
FAU - Lee, Jennifer J
AU  - Lee JJ
AD  - Abramson Cancer Center and Department of Medicine.
FAU - Nicastri, Michael C
AU  - Nicastri MC
AD  - Department of Chemistry, College of Arts & Sciences, University of Pennsylvania, 
      Philadelphia, Pennsylvania, USA.
FAU - Harper, Sandra L
AU  - Harper SL
AD  - Wistar Institute, Philadelphia, Pennsylvania, USA.
FAU - Ronghe, Amruta
AU  - Ronghe A
AD  - Wistar Institute, Philadelphia, Pennsylvania, USA.
FAU - Jain, Vaibhav
AU  - Jain V
AD  - Abramson Cancer Center and Department of Medicine.
FAU - Winkler, Jeffrey D
AU  - Winkler JD
AD  - Department of Chemistry, College of Arts & Sciences, University of Pennsylvania, 
      Philadelphia, Pennsylvania, USA.
FAU - Speicher, David W
AU  - Speicher DW
AD  - Wistar Institute, Philadelphia, Pennsylvania, USA.
FAU - Mastio, Jerome
AU  - Mastio J
AD  - Wistar Institute, Philadelphia, Pennsylvania, USA.
FAU - Gimotty, Phyllis A
AU  - Gimotty PA
AD  - Department of Biostatistics, Epidemiology & Informatics, Perelman School of 
      Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Xu, Xiaowei
AU  - Xu X
AD  - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Wherry, E John
AU  - Wherry EJ
AD  - Department of Systems Pharmacology and Translational Therapeutics and Penn 
      Institute for Immunology, and.
FAU - Gabrilovich, Dmitry I
AU  - Gabrilovich DI
AD  - Wistar Institute, Philadelphia, Pennsylvania, USA.
FAU - Amaravadi, Ravi K
AU  - Amaravadi RK
AD  - Abramson Cancer Center and Department of Medicine.
LA  - eng
GR  - P01 CA165997/CA/NCI NIH HHS/United States
GR  - P30 CA010815/CA/NCI NIH HHS/United States
GR  - P01 CA114046/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - R01 CA198015/CA/NCI NIH HHS/United States
GR  - P50 CA174523/CA/NCI NIH HHS/United States
GR  - R01 CA169134/CA/NCI NIH HHS/United States
GR  - P30 CA016520/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200903
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Antibodies)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 4QWG6N8QKH (Hydroxychloroquine)
RN  - 77238-31-4 (Interferon-beta)
RN  - EC 2.7.7.- (Nucleotidyltransferases)
RN  - EC 2.7.7.- (cGAS protein, mouse)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
EIN - JCI Insight. 2022 Oct 24;7(20):. PMID: 36278493
MH  - Animals
MH  - Antibodies/immunology
MH  - Antineoplastic Combined Chemotherapy Protocols
MH  - Enzyme Inhibitors/administration & dosage/*pharmacology/therapeutic use
MH  - Hydroxychloroquine/administration & dosage/*pharmacology/therapeutic use
MH  - Immune Checkpoint Inhibitors/administration & dosage/pharmacology/*therapeutic 
      use
MH  - Interferon-beta/metabolism
MH  - Macrophages/drug effects/immunology
MH  - Melanoma/*drug therapy/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nucleotidyltransferases/metabolism
MH  - Programmed Cell Death 1 Receptor/*antagonists & inhibitors/immunology
MH  - RAW 264.7 Cells
MH  - T-Lymphocytes/immunology
MH  - Thiolester Hydrolases/*antagonists & inhibitors/genetics/metabolism
MH  - Tumor Cells, Cultured
PMC - PMC7526447
OTO - NOTNLM
OT  - Autophagy
OT  - Lysosomes
OT  - Melanoma
OT  - Oncology
OT  - Therapeutics
COIS- Conflict of interest: RKA and JDW are cofounders of Pinpoint Therapeutics and 
      inventors on patents covering dimeric chloroquine compounds (US Patent Numbers 
      61/480,64; 62/034,897; and 15/567,187). RKA is a consultant for Sprint 
      Bioscience, Immunaccel, and Array BioPharma.
EDAT- 2020/08/12 06:00
MHDA- 2021/05/22 06:00
PMCR- 2020/09/03
CRDT- 2020/08/12 06:00
PHST- 2019/09/04 00:00 [received]
PHST- 2020/07/24 00:00 [accepted]
PHST- 2020/08/12 06:00 [pubmed]
PHST- 2021/05/22 06:00 [medline]
PHST- 2020/08/12 06:00 [entrez]
PHST- 2020/09/03 00:00 [pmc-release]
AID - 133225 [pii]
AID - 10.1172/jci.insight.133225 [doi]
PST - epublish
SO  - JCI Insight. 2020 Sep 3;5(17):e133225. doi: 10.1172/jci.insight.133225.