Dataset Information

Natural killer cell and stroma abundance are independently prognostic and predict gastric cancer chemotherapy benefit.

ABSTRACT: BACKGROUNDSpecific features of the tumor microenvironment (TME) may provide useful prognostic information. We conducted a systematic investigation of the cellular composition and prognostic landscape of the TME in gastric cancer.METHODSWe evaluated the prognostic significance of major stromal and immune cells within the TME. We proposed a composite TME-based risk score and tested it in 6 independent cohorts of 1678 patients with gene expression or IHC measurements. Further, we devised a patient classification system based on TME characteristics.RESULTSWe identified NK cells, fibroblasts, and endothelial cells as the most robust prognostic markers. The TME risk score combining these cell types was an independent prognostic factor when adjusted for clinicopathologic variables (gene expression, HR [95% CI], 1.42 [1.22-1.66]; IHC, 1.34 [1.24-1.45], P < 0.0001). Higher TME risk scores consistently associated with worse survival within every pathologic stage (HR range, 2.18-3.11, P < 0.02) and among patients who received surgery only. The TME risk score provided additional prognostic value beyond stage, and combination of the two improved prognostication accuracy (likelihood-ratio test ?2 = 235.4 vs. 187.6, P < 0.0001; net reclassification index, 23%). The TME risk score can predict the survival benefit of adjuvant chemotherapy in nonmetastatic patients (stage I-III) (interaction test, P < 0.02). Patients were divided into 4 TME subtypes that demonstrated distinct genetic and molecular patterns and complemented established genomic and molecular subtypes.CONCLUSIONWe developed and validated a TME-based risk score as an independent prognostic and predictive factor, which has the potential to guide personalized management of gastric cancer.FUNDINGThis project is partially supported by NIH grant 1R01 CA222512.

SUBMITTER: Li B

PROVIDER: S-EPMC7253031 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Natural killer cell and stroma abundance are independently prognostic and predict gastric cancer chemotherapy benefit.

Li Bailiang B Jiang Yuming Y Li Guoxin G Fisher George A GA Li Ruijiang R

JCI insight 20200507 9

BACKGROUNDSpecific features of the tumor microenvironment (TME) may provide useful prognostic information. We conducted a systematic investigation of the cellular composition and prognostic landscape of the TME in gastric cancer.METHODSWe evaluated the prognostic significance of major stromal and immune cells within the TME. We proposed a composite TME-based risk score and tested it in 6 independent cohorts of 1678 patients with gene expression or IHC measurements. Further, we devised a patient ...[more]

PMID: 32229725

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Project description:BackgroundWe previously established a 53-gene prognostic signature for overall survival (OS) of gastric cancer patients. This retrospective multi-center study aimed to develop a clinically applicable gene expression detection assay and to investigate the prognostic value of this signature.MethodsA TCGA gastric adenocarcinoma cohort (TCGA-STAD) was used for comparing 53-gene signature with other gene signatures. A high-throughput mRNA hybridization gene expression assay was developed to quantify the expression of 53-genes in formalin-fixed paraffin-embedded tissues of 540 patients enrolled from three hospitals. 180 patents were randomly selected from two hospitals to build a prognostic prediction model based on the 53-gene signature using leave-p-out (one-third out) cross-validation method together with Cox regression and Kaplan-Meier analysis, and the model was assessed on three validation cohorts.FindingsIn the evaluation phase, studies based on TCGA-STAD showed that the 53-gene signature was significantly superior to other three prognostic signatures and was independent of TCGA molecular subtypes and clinical factors. For clinical validation and utility, the prognostic scores were generated using the newly developed assay, which was reliable and sensitive, in 100 sampling training sets and were significantly associated with OS in 100 sampling validation sets. The scores were significantly associated with OS in three independent and combined validation cohorts, and in patients with stages II and III/IV. The multivariate Cox regression demonstrated that the prognostic power of the score was independent of clinical factors, consistent with those findings in the TCGA dataset. Finally, patients with good prognostic scores exhibited significantly a better 5-year OS rate from adjuvant FOLFOX chemotherapy after surgery than from other chemotherapies.InterpretationThe 53-gene prognostic score system is clinically applicable for predicting the OS of patients independent of clinical factors in gastric cancers, which could also be a promising predictive biomarker for FOLFOX regimen.FundingChinese National Science and Technology, National Natural Science Foundation and Natural Science Foundation of Jiangsu Province.

Project description:BackgroundInfluenza infects tens of millions of people every year in the USA. Other than notable risk groups, such as children and the elderly, it is difficult to predict what subpopulations are at higher risk of infection. Viral challenge studies, where healthy human volunteers are inoculated with live influenza virus, provide a unique opportunity to study infection susceptibility. Biomarkers predicting influenza susceptibility would be useful for identifying risk groups and designing vaccines.MethodsWe applied cell mixture deconvolution to estimate immune cell proportions from whole blood transcriptome data in four independent influenza challenge studies. We compared immune cell proportions in the blood between symptomatic shedders and asymptomatic nonshedders across three discovery cohorts prior to influenza inoculation and tested results in a held-out validation challenge cohort.ResultsNatural killer (NK) cells were significantly lower in symptomatic shedders at baseline in both discovery and validation cohorts. Hematopoietic stem and progenitor cells (HSPCs) were higher in symptomatic shedders at baseline in discovery cohorts. Although the HSPCs were higher in symptomatic shedders in the validation cohort, the increase was statistically nonsignificant. We observed that a gene associated with NK cells, KLRD1, which encodes CD94, was expressed at lower levels in symptomatic shedders at baseline in discovery and validation cohorts. KLRD1 expression in the blood at baseline negatively correlated with influenza infection symptom severity. KLRD1 expression 8 h post-infection in the nasal epithelium from a rhinovirus challenge study also negatively correlated with symptom severity.ConclusionsWe identified KLRD1-expressing NK cells as a potential biomarker for influenza susceptibility. Expression of KLRD1 was inversely correlated with symptom severity. Our results support a model where an early response by KLRD1-expressing NK cells may control influenza infection.

Dataset Information

Natural killer cell and stroma abundance are independently prognostic and predict gastric cancer chemotherapy benefit.

Publications

Natural killer cell and stroma abundance are independently prognostic and predict gastric cancer chemotherapy benefit.

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