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Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy.

ABSTRACT: There is ample evidence that neoadjuvant chemotherapy of breast carcinoma is particularly efficient if the tumor presents signs of either a pre-existent or therapy-induced anticancer immune response. Antineoplastic chemotherapies are particularly beneficial if they succeed in inducing immunogenic cell death, hence converting the tumor into its own therapeutic vaccine. Immunogenic cell death is characterized by a pre-mortem stress response including endoplasmic reticulum stress and autophagy. Based on these premises, we attempted to identify metagenes that reflect an intratumoral immune response or local stress responses in the transcriptomes of breast cancer patients. No consistent correlations between immune- and stress-related metagenes could be identified across several cohorts of patients, representing a total of 1045 mammary carcinomas. Moreover, few if any, of the stress-relevant metagenes influenced the probability of pathological complete response to chemotherapy. In contrast, several immune-relevant metagenes had a significant positive impact on response rates. This applies in particular to a CXCL13-centered, highly reproducible metagene signature reflecting the intratumoral presence of interferon-?-producing T cells.

SUBMITTER: Stoll G

PROVIDER: S-EPMC4004621 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy.

Stoll Gautier G Enot David D Mlecnik Bernhard B Galon Jérôme J Zitvogel Laurence L Kroemer Guido G

Oncoimmunology 20140101 1

There is ample evidence that neoadjuvant chemotherapy of breast carcinoma is particularly efficient if the tumor presents signs of either a pre-existent or therapy-induced anticancer immune response. Antineoplastic chemotherapies are particularly beneficial if they succeed in inducing immunogenic cell death, hence converting the tumor into its own therapeutic vaccine. Immunogenic cell death is characterized by a pre-mortem stress response including endoplasmic reticulum stress and autophagy. Bas ...[more]

PMID: 24790795

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Project description:BackgroundThe understanding of the factors causing decreased overall survival (OS) in older patients compared to younger patients in lung adenocarcinoma (LUAD) remains.MethodsGene expression profiles of LUAD were obtained from publicly available databases by Kaplan-Meier analysis was performed to determine whether age was associated with patient OS. The immune cell composition in the tumor microenvironment (TME) was evaluated using CIBERSORT. The fraction of stromal and immune cells in tumor samples were also using assessed using multiple tools including ESTIMATE, EPIC, and TIMER. Differentially expressed genes (DEGs) from the RNA-Seq data that were associated with age and immune cell composition were identified using the R package DEGseq. A 22-gene signature composed of DEGs associated with age and immune cell composition that predicted OS were constructed using Least Absolute Shrinkage and Selection Operator (LASSO).ResultsIn The Cancer Genome Atlas (TCGA)-LUAD dataset, we found that younger patients (≤70) had a significant better OS compared to older patients (>70). In addition, older patients had significantly higher expression of immune checkpoint proteins including inhibitory T cell receptors and their ligands. Moreover, analyses using multiple bioinformatics tools showed increased immune infiltration, including CD4+ T cells, in older patients compared to younger patients. We identified a panel of genes differentially expressed between patients >70 years compared to those ≤70 years, as well as between patients with high or low immune scores and selected 84 common genes to construct a prognostic gene signature. A risk score calculated based on 22 genes selected by LASSO predicted 1, 3, and 5-year OS, with an area under the curve (AUC) of 0.72, 0.72, 0.69, receptively, in TCGA-LUAD dataset and an independent validation dataset available from the European Genome-phenome Archive (EGA).ConclusionOur results demonstrate that age contributes to OS of LUAD patients atleast in part through its association with immune infiltration in the TME.

Project description:The immune system is crucial in regulating colorectal cancer (CRC) tumorigenesis. Identification of immune-related transcriptomic signatures derived from the peripheral blood of patients with CRC would provide insights into CRC pathogenesis, and suggest novel clues to potential immunotherapy strategies for the disease. The present study collected blood samples from 59 patients with CRC and 62 healthy control patients and performed whole blood gene expression profiling using microarray hybridization. Immune-related gene expression signatures for CRC were identified from immune gene datasets, and an algorithmic predictive model was constructed for distinguishing CRC from controls. Model performance was characterized using an area under the receiver operating characteristic curve (ROC AUC). Functional categories for CRC-specific gene expression signatures were determined using gene set enrichment analyses. A Kaplan-Meier plotter survival analysis was also performed for CRC-specific immune genes in order to characterize the association between gene expression and CRC prognosis. The present study identified five CRC-specific immune genes [protein phosphatase 3 regulatory subunit Bα (PPP3R1), amyloid β precursor protein, cathepsin H, proteasome activator subunit 4 and DEAD-Box Helicase 3 X-Linked]. A predictive model based on this five-gene panel showed good discriminatory power (independent test set sensitivity, 83.3%; specificity, 94.7%, accuracy, 89.2%; ROC AUC, 0.96). The candidate genes were involved in pathways associated with 'adaptive immune responses', 'innate immune responses' and 'cytokine signaling'. The survival analysis found that a high level of PPP3R1 expression was associated with a poor CRC prognosis. The present study identified five CRC-specific immune genes that were potential diagnostic biomarkers for CRC. The biological function analysis indicated a close association between CRC pathogenesis and the immune system, and may reveal more information about the immunogenic and pathogenic mechanisms driving CRC in the future. Overall, the association between PPP3R1 expression and survival of patients with CRC revealed potential new targets for CRC immunotherapy.

Project description:The incidence of oesophageal adenocarcinoma (OeC) has been increasing rapidly in most Western countries during the last few decades. Although multimodal treatment combining pre-operative chemotherapy with radical surgical resection has become the standard of care in the UK for all patients with locally advanced resectable disease, the 5-year survival rate in this patient group is less than 25%. Only 30% of all patients will benefit from pre-operative chemotherapy. Hence, there is an urgent clinical need to identify genomic markers that allow stratification of patients for a more individualised therapy approach. The goal of this study is to use whole genome high-resolution array CGH to examine the DNA copy number profile of a subset of OeC patients recruited into the OE02 trial and establish it’s relationship with clinicopathological variables including pathological tumor regression and patient survival. High-resolution array CGH analysis was conducted on 84 formalin fixed paraffin embedded resection samples obtained from subjects enrolled in the Oe02 trial. We compared the DNA copy number profiles between patients treated with chemotherapy and surgery and those treated with surgery alone. DNA copy number entropy was assessed to identify differences in overall copy number aberrations between the two treatment groups. Furthermore, the association between DNA copy number aberrations and tumor regression grade was investigated. The genetic make-up of OeCs investigated in the current study proved to be highly complex reducing our ability to determine the background normal copy number level in a tumor sample. Using DNA copy number entropy as a measure to compare sample profiles, we identified significant treatment arm specific DNA copy number aberration patterns predominantly in chromosome 1 and 5. High DNA copy number entropy was associated with longer overall survival. Differential DNA copy number entropy was observed between the two treatment groups, and the positions of the driving DNA regions were identified. To our surprise, the differences between the treatment groups went unnoticed when a standard test was applied. We also found that the DNA copy number entropy was strongly correlated with patients’ overall survival and clinicopathological characteristics. To the best of our knowledge, this is the first study in OeC quantitatively showed that the tumor heterogeneity was reduced by chemotherapy. And, the observed tumor heterogeneity was shown to has prognostic value. However, further research is needed to narrow down these regions to a few driving genes/probes that may aid in predicting whether a new patient will benefit from chemotherapy.

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Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy.

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Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy.

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