4-(N)-Docosahexaenoyl 2', 2'-difluorodeoxycytidine induces immunogenic cell death in colon and pancreatic carcinoma models as a single agent.
Animals
Female
Humans
Male
Antibodies, Monoclonal
/ administration & dosage
Antineoplastic Agents
/ immunology
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Cell Line, Tumor
Colonic Neoplasms
/ drug therapy
Drug Screening Assays, Antitumor
Gene Expression Regulation, Neoplastic
/ drug effects
HMGB1 Protein
/ metabolism
Immune Checkpoint Inhibitors
/ administration & dosage
Immunogenic Cell Death
/ drug effects
Mice, Inbred BALB C
Mice, Inbred C57BL
Pancreatic Neoplasms
/ drug therapy
Programmed Cell Death 1 Receptor
/ immunology
Pancreatic Neoplasms
Anti-PD-1 mAbs
Cancer
Gemcitabine
Immunogenic cell death
Polyunsaturated fatty acid
RNA expression
Journal
Cancer chemotherapy and pharmacology
ISSN: 1432-0843
Titre abrégé: Cancer Chemother Pharmacol
Pays: Germany
ID NLM: 7806519
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
08
04
2021
accepted:
14
10
2021
pubmed:
27
10
2021
medline:
23
2
2022
entrez:
26
10
2021
Statut:
ppublish
Résumé
Docosahexaenoyl difluorodeoxycytidine (DHA-dFdC) is an amide with potent, broad-spectrum antitumor activity. In the present study, DHA-dFdC's ability to induce immunogenic cell death (ICD) was tested using CT26 mouse colorectal cancer cells, an established cell line commonly used for identifying ICD inducers, as well as Panc-02 mouse pancreatic cancer cells. The three primary surrogate markers of ICD (i.e., calreticulin (CRT) surface translocation, ATP release, and high mobility group box 1 protein (HMGB1) release) were measured in vitro. To confirm DHA-dFdC's ability to induce ICD in vivo, the gold standard mouse vaccination studies were conducted using both CT26 and Panc-02 models. Additionally, the effect of DHA-dFdC on tumor response to anti-programmed cell death protein 1 monoclonal antibody (anti-PD-1 mAb) were tested in mice with pre-established Panc-02 tumors. RNA sequencing experiments were conducted on PANC-1 human pancreatic cancer cells treated with DHA-dFdC, dFdC, or vehicle control in vitro. DHA-dFdC elicited CRT surface translocation and ATP and HMGB1 release in both cell lines. Immunization of mice with CT26 or Panc-02 cells pretreated with DHA-dFdC prevented or delayed the development of corresponding secondary live challenge tumor. DHA-dFdC enabled Panc-02 tumors to respond to anti-PD-1 mAb. RNA sequencing experiments revealed that DHA-dFdC and dFdC differentially impacted genes related to the KRAS, TP53, and inflammatory pathways, and DHA-dFdC enriched for the unfolded protein response (UPR) compared to control, providing insight into DHA-dFdC's potential mechanism of inducing ICD. DHA-dFdC is a bona fide ICD inducer and can render pancreatic tumors responsive to anti-PD-1 mAb therapy.
Identifiants
pubmed: 34698902
doi: 10.1007/s00280-021-04367-2
pii: 10.1007/s00280-021-04367-2
pmc: PMC8741741
mid: NIHMS1759073
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antineoplastic Agents
0
HMGB1 Protein
0
HMGB1 protein, mouse
0
Immune Checkpoint Inhibitors
0
Pdcd1 protein, mouse
0
Programmed Cell Death 1 Receptor
0
Docosahexaenoyl difluorodeoxycytidine
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
59-69Subventions
Organisme : NCI NIH HHS
ID : R01 CA135274
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA179362
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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