Loss of cancer cell STAT1 improves response to radiation therapy and promotes T cell activation in head and neck squamous cell carcinoma.
Cancer immunology
HNSCC
Interferon signaling
Radiation therapy
STAT1
Tumor microenvironment
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
May 2022
May 2022
Historique:
received:
03
07
2021
accepted:
10
09
2021
pubmed:
25
9
2021
medline:
21
4
2022
entrez:
24
9
2021
Statut:
ppublish
Résumé
Resistance to radiation therapy (RT) remains an obstacle in HPV-negative head and neck squamous cell carcinomas (HNSCCs)-even with a combined RT-immunotherapy approach. Jak-Stat proteins have long been studied for both their immune regulatory role in the host immune response as well as their cancer cell signaling role in shaping the tumor microenvironment (TME). Here, we identify STAT1 as a mediator of radioresistance in HPV-negative preclinical mouse models of HNSCC, by which knockout of STAT1 in the cancer cell (STAT1 KO)-but not in the host-resulted in decreased tumor growth alongside increased immune activation. We show that RT increases STAT1/pSTAT1 expression, which may act as a marker of radioresistance. Whereas RT increased JAK-STAT and interferon (IFN) signaling, transcriptomic analysis revealed that STAT1 KO in the cancer cell resulted in decreased expression of IFN-associated genes of resistance. In vitro experiments showed that STAT1 KO increased T cell chemoattraction and decreased baseline growth. These results indicate that STAT1 may serve a tumor-promoting role in the cancer cell and will inform biomarker development and treatment regimens for HNSCC incorporating RT.
Identifiants
pubmed: 34559306
doi: 10.1007/s00262-021-03059-3
pii: 10.1007/s00262-021-03059-3
pmc: PMC9987617
mid: NIHMS1866752
doi:
Substances chimiques
STAT1 Transcription Factor
0
STAT1 protein, human
0
Stat1 protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1049-1061Subventions
Organisme : NCI NIH HHS
ID : P50 CA261605
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028529
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028282
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028529-01
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028282-01
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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