DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation

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 pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Molecular and functional characterization of ferritin in abalone Haliotis diversicolor supertexta

Ferritin is an iron storage protein that plays a key role in the processes of physiology and pathology.In the present study,the authors reported the ferritin gene from abalone Haliotis diversicolor supertexta,which we named hds-ferritin.The full-length of hds-ferritin cDNA consisted of 879 bp with an ORF encoding a 171 amino acids.Amino acid sequence analysis revealed that hds-ferritin shared highly homology with other species.Real time PCR and western blot analysis showed that hds-ferritin was distributed ubiquitously in abalone tissues and had the highest expression level in digestive glands,but its transcripts are not modified remarkably by the stimulation with LPS.The recombinant protein was successfully expressed in Escherichia coli BL21 (DE3),and the titre of anti-ferritin antibody was about 1∶14000.The effects of ROS and RNS on ferritin were analyzed in the present study.The results showed that H2O2 played an important role in decreasing hds-ferritin,however NO cation appeared to have a protecting effect on H2O2-medied reduction of hds-ferritin.