Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 Mar 2022
01 Mar 2022
Historique:
received:
30
07
2021
revised:
01
10
2021
accepted:
29
11
2021
pubmed:
5
12
2021
medline:
16
4
2022
entrez:
4
12
2021
Statut:
ppublish
Résumé
Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden. PDAC patient tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following radiotherapy. Genetically engineered mouse strains in combination with orthotopic tumor models of PDAC were used to characterize disease progression. Flow cytometry was used to analyze tumor infiltrating, circulating, and nodal immune populations. We demonstrate that although radiotherapy increases the infiltration and activation of dendritic cells (DC), it also increases the infiltration of regulatory T cells (Treg) while failing to recruit natural killer (NK) and CD8 T cells in PDAC patient tissue samples. In murine orthotopic tumor models, we show that genetic and pharmacologic depletion of Tregs and NK cells enhances and attenuates response to radiotherapy, respectively. We further demonstrate that targeted inhibition of STAT3 on Tregs results in improved control of local and distant disease progression and enhanced NK-mediated immunosurveillance of metastasis. Moreover, combination treatment of STAT3 antisense oligonucleotide (ASO) and radiotherapy invigorated systemic immune activation and conferred a survival advantage in orthotopic and metastatic tumor models. Finally, we show the response to STAT3 ASO + radiotherapy treatment is dependent on NK and DC subsets. Our results suggest targeting Treg-mediated immunosuppression is a critical step in mediating a response to treatment, and identifying NK cells as not only a prognostic marker of improved survival, but also as an effector population that functions to combat metastasis.
Identifiants
pubmed: 34862244
pii: 1078-0432.CCR-21-2767
doi: 10.1158/1078-0432.CCR-21-2767
pmc: PMC8898296
mid: NIHMS1763172
doi:
Substances chimiques
STAT3 Transcription Factor
0
STAT3 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1013-1026Subventions
Organisme : NCI NIH HHS
ID : P50 CA261605
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028529
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS048154
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116073
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA174648
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028282
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI131662
Pays : United States
Organisme : NIH HHS
ID : S10 OD027023
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
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