Cargando…
The cGAS/STING/IFN-1 Response in Squamous Head and Neck Cancer Cells after Genotoxic Challenges and Abrogation of the ATR-Chk1 and Fanconi Anemia Axis
Locally advanced head and neck squamous cell carcinomas (HNSCC) are often refractory to platinum-based radiochemotherapy and new immuno-oncological strategies. To stimulate immunogenic antitumor responses in HNSCC patients, we investigated the cGAS/STING/IFN-1 signaling pathway after genotoxic treat...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10573837/ https://www.ncbi.nlm.nih.gov/pubmed/37834346 http://dx.doi.org/10.3390/ijms241914900 |
_version_ | 1785120553700425728 |
---|---|
author | Zahnreich, Sebastian El Guerzyfy, Soumia Kaufmann, Justus Schmidberger, Heinz |
author_facet | Zahnreich, Sebastian El Guerzyfy, Soumia Kaufmann, Justus Schmidberger, Heinz |
author_sort | Zahnreich, Sebastian |
collection | PubMed |
description | Locally advanced head and neck squamous cell carcinomas (HNSCC) are often refractory to platinum-based radiochemotherapy and new immuno-oncological strategies. To stimulate immunogenic antitumor responses in HNSCC patients, we investigated the cGAS/STING/IFN-1 signaling pathway after genotoxic treatments and concomitant abrogation of the DNA damage response (DDR). For this purpose, FaDu and UM-SCC1 cells were exposed to X-rays or cisplatin and treated with an ATR or Chk1 inhibitor, or by Fanconi anemia gene A knockout (FANCA ko). We assessed clonogenic survival, cell cycle regulation, micronuclei, free cytosolic double-stranded DNA, and the protein expression and activity of the cGAS/STING/IFN-1 pathway and related players. Cell survival, regulation of G2/M arrest, and formation of rupture-prone cGAS-positive micronuclei after genotoxic treatments were most affected by ATR inhibition and FANCA ko. In UM-SCC-1 cells only, 8 Gy X-rays promoted IFN-1 expression unaltered by abrogation of the DDR or concomitant increased TREX1 expression. At a higher dose of 20 Gy, this effect was observed only for concurrent Chk1- or ATR-inhibition. FANCA ko or cisplatin treatment was ineffective in this regard. Our observations open new perspectives for the enhancement of cGAS/STING/IFN-1-mediated antitumor immune response in HNSCC by hypofractionated or stereotactic radiotherapy concepts in multimodal settings with immuno-oncological strategies. |
format | Online Article Text |
id | pubmed-10573837 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-105738372023-10-14 The cGAS/STING/IFN-1 Response in Squamous Head and Neck Cancer Cells after Genotoxic Challenges and Abrogation of the ATR-Chk1 and Fanconi Anemia Axis Zahnreich, Sebastian El Guerzyfy, Soumia Kaufmann, Justus Schmidberger, Heinz Int J Mol Sci Article Locally advanced head and neck squamous cell carcinomas (HNSCC) are often refractory to platinum-based radiochemotherapy and new immuno-oncological strategies. To stimulate immunogenic antitumor responses in HNSCC patients, we investigated the cGAS/STING/IFN-1 signaling pathway after genotoxic treatments and concomitant abrogation of the DNA damage response (DDR). For this purpose, FaDu and UM-SCC1 cells were exposed to X-rays or cisplatin and treated with an ATR or Chk1 inhibitor, or by Fanconi anemia gene A knockout (FANCA ko). We assessed clonogenic survival, cell cycle regulation, micronuclei, free cytosolic double-stranded DNA, and the protein expression and activity of the cGAS/STING/IFN-1 pathway and related players. Cell survival, regulation of G2/M arrest, and formation of rupture-prone cGAS-positive micronuclei after genotoxic treatments were most affected by ATR inhibition and FANCA ko. In UM-SCC-1 cells only, 8 Gy X-rays promoted IFN-1 expression unaltered by abrogation of the DDR or concomitant increased TREX1 expression. At a higher dose of 20 Gy, this effect was observed only for concurrent Chk1- or ATR-inhibition. FANCA ko or cisplatin treatment was ineffective in this regard. Our observations open new perspectives for the enhancement of cGAS/STING/IFN-1-mediated antitumor immune response in HNSCC by hypofractionated or stereotactic radiotherapy concepts in multimodal settings with immuno-oncological strategies. MDPI 2023-10-04 /pmc/articles/PMC10573837/ /pubmed/37834346 http://dx.doi.org/10.3390/ijms241914900 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zahnreich, Sebastian El Guerzyfy, Soumia Kaufmann, Justus Schmidberger, Heinz The cGAS/STING/IFN-1 Response in Squamous Head and Neck Cancer Cells after Genotoxic Challenges and Abrogation of the ATR-Chk1 and Fanconi Anemia Axis |
title | The cGAS/STING/IFN-1 Response in Squamous Head and Neck Cancer Cells after Genotoxic Challenges and Abrogation of the ATR-Chk1 and Fanconi Anemia Axis |
title_full | The cGAS/STING/IFN-1 Response in Squamous Head and Neck Cancer Cells after Genotoxic Challenges and Abrogation of the ATR-Chk1 and Fanconi Anemia Axis |
title_fullStr | The cGAS/STING/IFN-1 Response in Squamous Head and Neck Cancer Cells after Genotoxic Challenges and Abrogation of the ATR-Chk1 and Fanconi Anemia Axis |
title_full_unstemmed | The cGAS/STING/IFN-1 Response in Squamous Head and Neck Cancer Cells after Genotoxic Challenges and Abrogation of the ATR-Chk1 and Fanconi Anemia Axis |
title_short | The cGAS/STING/IFN-1 Response in Squamous Head and Neck Cancer Cells after Genotoxic Challenges and Abrogation of the ATR-Chk1 and Fanconi Anemia Axis |
title_sort | cgas/sting/ifn-1 response in squamous head and neck cancer cells after genotoxic challenges and abrogation of the atr-chk1 and fanconi anemia axis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10573837/ https://www.ncbi.nlm.nih.gov/pubmed/37834346 http://dx.doi.org/10.3390/ijms241914900 |
work_keys_str_mv | AT zahnreichsebastian thecgasstingifn1responseinsquamousheadandneckcancercellsaftergenotoxicchallengesandabrogationoftheatrchk1andfanconianemiaaxis AT elguerzyfysoumia thecgasstingifn1responseinsquamousheadandneckcancercellsaftergenotoxicchallengesandabrogationoftheatrchk1andfanconianemiaaxis AT kaufmannjustus thecgasstingifn1responseinsquamousheadandneckcancercellsaftergenotoxicchallengesandabrogationoftheatrchk1andfanconianemiaaxis AT schmidbergerheinz thecgasstingifn1responseinsquamousheadandneckcancercellsaftergenotoxicchallengesandabrogationoftheatrchk1andfanconianemiaaxis AT zahnreichsebastian cgasstingifn1responseinsquamousheadandneckcancercellsaftergenotoxicchallengesandabrogationoftheatrchk1andfanconianemiaaxis AT elguerzyfysoumia cgasstingifn1responseinsquamousheadandneckcancercellsaftergenotoxicchallengesandabrogationoftheatrchk1andfanconianemiaaxis AT kaufmannjustus cgasstingifn1responseinsquamousheadandneckcancercellsaftergenotoxicchallengesandabrogationoftheatrchk1andfanconianemiaaxis AT schmidbergerheinz cgasstingifn1responseinsquamousheadandneckcancercellsaftergenotoxicchallengesandabrogationoftheatrchk1andfanconianemiaaxis |