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

被引:3
|
作者
Zahnreich, Sebastian [1 ]
El Guerzyfy, Soumia [1 ]
Kaufmann, Justus [1 ]
Schmidberger, Heinz [1 ]
机构
[1] Johannes Gutenberg Univ Mainz, Univ Med Ctr Johannes Gutenberg, Dept Radiat Oncol & Radiat Therapy, D-55131 Mainz, Germany
关键词
head and neck cancer; ionizing radiation; cisplatin; cGAS; STING; type; 1; interferons; cytosolic DNA; ATR; Chk1; Fanconi anemia; LOCALLY ADVANCED HEAD; DNA; CARCINOMA; PATHWAY; P53; PEMBROLIZUMAB; GENES; MULTICENTER; EXPRESSION; RECURRENT;
D O I
10.3390/ijms241914900
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:16
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