An antigen processing and presentation signature for prognostic evaluation and immunotherapy selection in advanced gastric cancer

Abstract

ObjectiveThe aim of the study was to propose a signature based on genes associated with antigen processing and presentation (APscore) to predict prognosis and response to immune checkpoint inhibitors (ICIs) in advanced gastric cancer (aGC).BackgroundHow antigen presentation-related genes affected the immunotherapy response and whether they could predict the clinical outcomes of the immune checkpoint inhibitor (ICI) in aGC remain largely unknown.MethodsIn this study, an aGC cohort (Kim cohort, RNAseq, N=45) treated by ICIs, and 467 aGC patients from seven cohorts were conducted to investigate the value of the APscore predicting the prognosis and response to ICIs. Subsequently, the associations of the APscore with the tumor microenvironment (TME), molecular characteristics, clinical features, and somatic mutation variants in aGC were assessed. The area under the receiver operating characteristic curve (AUROC) of the APscore was analyzed to estimate response to ICIs. Cox regression or Log-rank test was used to estimate the prognosis of aGC patients.ResultsThe APscore constructed by principal component analysis algorithms was an effective predictive biomarker of the response to ICIs in the Kim cohort and 467 aGC patients (Kim: AUC =0.85, 95% CI: 0.69–1.00; 467 aGC: AUC =0.69, 95% CI: 0.63–0.74). The APscore also was a prognostic biomarker in 467 aGC patients (HR=1.73, 95% CI: 1.21−2.46). Inhibitory immunity, decreased TMB and low stromal scores were observed in the high APscore group, while activation of immunity, increased TMB, and high stromal scores were observed in the low APscore group. Next, we evaluated the value of several central genes in predicting the prognosis and response to ICIs in aGC patients, and verified them using immunogenic, transcriptomic, genomic, and multi-omics methods. Lastly, a predictive model built successfully discriminated patients with vs. without immunotherapy response and predicted the survival of aGC patients.ConclusionsThe APscore was a new biomarker for identifying high-risk aGC patients and patients with responses to ICIs. Exploration of the APscore and hub genes in multi-omics GC data may guide treatment decisions.

Cellular dynamics in tumour microenvironment along with lung cancer progression underscore spatial and evolutionary heterogeneity of neutrophil

“…On the contrary, closer interactions between neutrophils and Th1 cells and CTL through B2M-CD3D and B2M-KLRD1 pairs, involving in the AP pathway were observed in the tumour-free TDLN (Figure S9B and C). 57 The NicheNet method showed that, with neutrophils as signal transmitters in the tumour-invaded TDLNs, CCL3/CCL4-CCR1 pairs were also dominant in mediating the interactions between neutrophils and macrophages, consistent with the findings of CellChat analysis (Figures S9D and F). Furthermore, the target genes of neutrophils-macrophages/endothelial cells interactions were correlated with angiogenesis (e.g., VEGFA, VCAM1 and MMP14) and epithelial-mesenchymal transition (e.g., PDGFD, CXCL12 and IGF1) processes (Figures S9E and 9G).…”

“…On the contrary, closer interactions between neutrophils and Th1 cells and CTL through B2M–CD3D and B2M–KLRD1 pairs, involving in the AP pathway were observed in the tumour‐free TDLN (Figure S9B and C ). 57 …”

Immunotherapy and Cancer: The Multi-Omics Perspective

“…Shi et al proposed a Gluco-Immune Score by analyzing the TME where gastric cancer (GC) patients with high scores are beneficiaries of IT [ 21 ] as well as the use of a gene-based antigen processing and presentation signature (APscore) suggested by Wang et al [ 22 ]. The importance of TME in affecting responses to ICI were also underlined by Zeng at al.…”

Harnessing Immune Checkpoint Inhibitors Against Gastric Cancer: Charting the Course to Expanded Therapeutic Benefit

“…This mechanism allows cancer cells to evade the immune system and continue to proliferate. Strategies focused on enhancing antigen presentation may help reactivate anti-tumor immunity 163 . Presenting new neoantigens, which are unique to individual tumors, is another potential approach to improve the efficacy of gastric cancer treatment 163 .…”