RT Journal Article
SR Electronic
T1 DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation
JF Cancer Biology & Medicine
JO Cancer Biology & Medicine
FD China Anti-Cancer Association
SP 252
OP 266
DO 10.20892/j.issn.2095-3941.2023.0303
VO 21
IS 3
A1 Yan, Junya
A1 Wang, Shibo
A1 Zhang, Jing
A1 Yuan, Qiangqiang
A1 Gao, Xianchun
A1 Zhang, Nannan
A1 Pan, Yan
A1 Zhang, Haohao
A1 Liu, Kun
A1 Yu, Jun
A1 Lu, Linbin
A1 Liu, Hui
A1 Gao, Xiaoliang
A1 Zhao, Sheng
A1 Zhang, Wenyao
A1 Reyila, Abudurousuli
A1 Qi, Yu
A1 Zhang, Qiujin
A1 Cang, Shundong
A1 Lu, Yuanyuan
A1 Pan, Yanglin
A1 Kong, Yan
A1 Nie, Yongzhan
YR 2024
UL http://www.cancerbiomed.org/content/21/3/252.abstract
AB Objective: DNA damage response (DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation (DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor (ICI) therapy in gastrointestinal (GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes (CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients (81.8% vs. 8.8%; P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve (AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pan-cancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.The results shown here are in part based on data generated by The Cancer Genome Atlas project (TCGA, http://cancergenome.nih.gov/) and data available in published articles10,29–32. The raw sequence data from PUCH dataset reported in this paper have been deposited in the Genome Sequence Archive in National Genomics Data Center, Beijing Institute of Genomics (China National Center for Bioinformation), Chinese Academy of Sciences, under accession number HRA000524 that are publicly accessible at http://bigd.big.ac.cn/gsa-human.