Gene expression profiles for a prognostic immunoscore in gastric cancer

Abstract

Background: Increasing evidence has indicated an association between immune infiltration in gastric cancer and clinical outcome. However, reliable prognostic signatures, based on systematic assessments of the immune landscape inferred from bulk tumour transcriptomes, have not been established. The aim was to develop an immune signature, based on the cellular composition of the immune infiltrate inferred from bulk tumour transcriptomes, to improve the prognostic predictions of gastric cancer.

Methods: Twenty-two types of immune cell fraction were estimated based on large public gastric cancer cohorts from the Gene Expression Omnibus using CIBERSORT. An immunoscore based on the fraction of immune cell types was then constructed using a least absolute shrinkage and selection operator (LASSO) Cox regression model.

Results: Using the LASSO model, an immunoscore was established consisting of 11 types of immune cell fraction. In the training cohort (490 patients), significant differences were found between high- and low-immunoscore groups in overall survival across and within subpopulations with an identical TNM stage. Multivariable analysis revealed that the immunoscore was an independent prognostic factor (hazard ratio 1·92, 95 per cent c.i. 1·54 to 2·40). The prognostic value of the immunoscore was also confirmed in the validation (210) and entire (700) cohorts.

Conclusion: The proposed immunoscore represents a promising signature for estimating overall survival in patients with gastric cancer.

Figure 1

Flow chart of data collection and analysis. LASSO, least absolute shrinkage and selection operator

Figure 2

Construction of the immunoscore model. a Forest plots showing associations between different immune cell subsets and overall survival in the training cohort. Unadjusted hazard ratios are shown with 95 per cent confidence intervals. NK, natural killer. b Least absolute shrinkage and selection operator (LASSO) coefficient profiles of the fractions of 21 immune cell types. The dotted line indicates the value chosen by tenfold cross‐validation. Immune cell type: 1, M2 macrophages; 2, M1 macrophages; 3, M0 macrophages; 4, CD8+ T cells; 5, activated memory CD4+ T cells; 6, regulatory T cells; 7, neutrophils; 8, activated dendritic cells; 9, monocytes; 10, follicular helper T cells; 11, resting NK cells; 12, activated NK cells; 13, activated mast cells; 14, resting mast cells; 15, memory B cells; 16, naive B cells; 17, plasma cells; 18, γδ T cells; 19, eosinophils; 20, resting dendritic cells; 21, naive CD4+ T cells. c Tenfold cross‐validation for tuning parameter selection in the LASSO model. The partial likelihood deviance is plotted against log (λ), where λ is the tuning parameter. Partial likelihood deviance values are shown, with error bars representing s.e. The dotted vertical lines are drawn at the optimal values by minimum criteria and 1 – s.e. criteria. In b and c, the numbers above the graph represent the number of cell types involved in the LASSO model. d Immunoscore measured by time‐dependent receiver–operating characteristic (ROC) curves in the training cohort. The area under the ROC curve was 0·68, 0·69 and 0·72 for the immunoscore at 2, 3 and 5 years respectively

Figure 3

Survival impact of the immunoscore. a–d Kaplan–Meier curves for overall survival by immunoscore group in the training cohort (a), validation cohort (b) and entire cohort (c), and for patients with stage II–III gastric cancer in subgroups stratified by both receipt of adjuvant chemotherapy (CT) and immunoscore (d). Hazard ratios are shown with 95 per cent confidence intervals. P < 0·001 (log rank test)

Figure 4

a Forest plot showing the survival impact of immunoscore stratified by type of adjuvant chemotherapy (CT) among patients with stage II and III gastric cancer. Hazard ratios, with 95 per cent confidence intervals, are shown for the high immunoscore group versus the low immunoscore group. b Forest plot showing the benefit of CT in different immunoscore groups of patients with stage II and III gastric cancer. Hazard ratios, with 95 per cent confidence intervals, are shown for CT versus no CT in each immunoscore group. XP, xeloda plus cisplatin; LF, leucovorin plus fluorouracil