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Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression-based study.

ABSTRACT: Immune infiltration of colorectal cancer (CRC) is closely associated with clinical outcome. However, previous work has not accounted for the diversity of functionally distinct cell types that make up the immune response. In this study, based on a deconvolution algorithm (known as CIBERSORT) and clinical annotated expression profiles, we comprehensively analyzed the tumor-infiltrating immune cells present in CRC for the first time. The fraction of 22 immune cells subpopulations was evaluated to determine the associations between each cell type and survival and response to chemotherapy. As a result, profiles of immune infiltration vary significantly between paired cancer and paracancerous tissue and the variation could characterize the individual differences. Of the cell subpopulations investigated, tumors lacking M1 macrophages or with an increased number of M2 macrophages, eosinophils, and neutrophils were associated with the poor prognosis. Unsupervised clustering analysis using immune cell proportions revealed five subgroups of tumors, largely defined by the balance between macrophages M1, M2, and NK resting cells, with distinct survival patterns, and associated with well-established molecular subtype. Collectively, our data suggest that subtle differences in the cellular composition of the immune infiltrate in CRC appear to exist, and these differences are likely to be important determinants of both prognosis and response to treatment.

SUBMITTER: Xiong Y

PROVIDER: S-EPMC6144159 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression-based study.

Xiong Yongfu Y Wang Kang K Zhou He H Peng Linglong L You Wenxian W Fu Zhongxue Z Fu Zhongxue Z

Cancer medicine 20180816 9

Immune infiltration of colorectal cancer (CRC) is closely associated with clinical outcome. However, previous work has not accounted for the diversity of functionally distinct cell types that make up the immune response. In this study, based on a deconvolution algorithm (known as CIBERSORT) and clinical annotated expression profiles, we comprehensively analyzed the tumor-infiltrating immune cells present in CRC for the first time. The fraction of 22 immune cells subpopulations was evaluated to d ...[more]

PMID: 30117315

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Project description:BackgroundImmune infiltration of breast tumours is associated with clinical outcome. However, past work has not accounted for the diversity of functionally distinct cell types that make up the immune response. The aim of this study was to determine whether differences in the cellular composition of the immune infiltrate in breast tumours influence survival and treatment response, and whether these effects differ by molecular subtype.Methods and findingsWe applied an established computational approach (CIBERSORT) to bulk gene expression profiles of almost 11,000 tumours to infer the proportions of 22 subsets of immune cells. We investigated associations between each cell type and survival and response to chemotherapy, modelling cellular proportions as quartiles. We found that tumours with little or no immune infiltration were associated with different survival patterns according to oestrogen receptor (ER) status. In ER-negative disease, tumours lacking immune infiltration were associated with the poorest prognosis, whereas in ER-positive disease, they were associated with intermediate prognosis. Of the cell subsets investigated, T regulatory cells and M0 and M2 macrophages emerged as the most strongly associated with poor outcome, regardless of ER status. Among ER-negative tumours, CD8+ T cells (hazard ratio [HR] = 0.89, 95% CI 0.80-0.98; p = 0.02) and activated memory T cells (HR 0.88, 95% CI 0.80-0.97; p = 0.01) were associated with favourable outcome. T follicular helper cells (odds ratio [OR] = 1.34, 95% CI 1.14-1.57; p < 0.001) and memory B cells (OR = 1.18, 95% CI 1.0-1.39; p = 0.04) were associated with pathological complete response to neoadjuvant chemotherapy in ER-negative disease, suggesting a role for humoral immunity in mediating response to cytotoxic therapy. Unsupervised clustering analysis using immune cell proportions revealed eight subgroups of tumours, largely defined by the balance between M0, M1, and M2 macrophages, with distinct survival patterns by ER status and associations with patient age at diagnosis. The main limitations of this study are the use of diverse platforms for measuring gene expression, including some not previously used with CIBERSORT, and the combined analysis of different forms of follow-up across studies.ConclusionsLarge differences in the cellular composition of the immune infiltrate in breast tumours appear to exist, and these differences are likely to be important determinants of both prognosis and response to treatment. In particular, macrophages emerge as a possible target for novel therapies. Detailed analysis of the cellular immune response in tumours has the potential to enhance clinical prediction and to identify candidates for immunotherapy.

Project description:BACKGROUND:Broad copy number aberrations (BCNAs) represent a common form of genome instability in colorectal cancer (CRC). CRCs show large variations in their level of aneuploidy: microsatellite-instable (MSI) tumors are known to have a near-diploid karyotype while microsatellite-stable (MSS) tumors show high level of chromosomal instability. However, MSS tumors have great heterogeneity in the number of BCNAs, with a minor percentage of samples showing an almost normal karyotype. In the present work we subdivided MSS CRCs according to a "BCNA score" and characterized their transcriptome profiles, considered as a proxy to their phenotypic features. METHODS:Microsatellite testing, genome-wide DNA copy number and whole-transcript expression analysis (HTA) were performed on 33 tumor samples and 25 normal colonic tissue samples from 32 CRC patients. 15.1% of the samples were MSI tumors (n?=?5), whereas 84.9% were MSS tumors (n?=?28). Gene expression data of 34 additional MSI tumors was retrieved from a public functional genomics data repository. RESULTS:Using as a threshold the first quartile of the BCNA score distribution, MSS samples were classified as low-BCNA (LB, n?=?7) or high-BCNA (HB, n?=?21). LB tumors were enriched for mucinous CRCs and their gene-expression profile resembled that of MSI samples for what concerns a subset of genes involved in secretory processes, mucosal protection, and extracellular matrix remodeling. HB tumors were predominantly non-mucinous adenocarcinomas and showed overexpression of a subset of genes typical of surface colonocytes and EGF signaling. A large percentage of unclassified samples according to the consensus molecular subtypes (CMS) classifier was found in the LB group (43%), whereas 76% HB tumors belonged to CMS2. CONCLUSIONS:A classification of colorectal tumors based on the number of BCNAs identifies two groups of MSS tumors which differ for histopathology and gene expression profile. Such information can be exploited for its translational relevance in different aspects of CRC clinical management.

Project description:Background: Immune infiltration of head and neck cancer (HNC) highly correlated with the patient's prognosis. However, previous studies failed to explain the diversity of different cell types that make up the function of the immune response system. The aim of the study was to uncover the differences in immune phenotypes of the tumor microenvironment (TME) between HNC adjacent tumor tissues and tumor tissues using CIBERSORT method and explore their therapeutic implications. Method: In current work, we employed the CIBERSORT method to evaluate the relative proportions of immune cell profiling in 11 paired HNC and adjacent samples, and analyzed the correlation between immune cell infiltration and clinical information. The tumor-infiltrating immune cells of TCGA HNC cohort was analyzed for the first time. The fractions of LM22 immune cells were imputed to determine the correlation between each immune cell subpopulation and survival and response to chemotherapy. Three types of molecular classification were identified via "CancerSubtypes" R-package. The functional enrichment was analyzed in each subtype. Results: The profiles of immune infiltration in TCGA HNC cohort significantly vary between paired cancer and para-cancerous tissue and the variation could reflect the individual difference. Total Macrophage, Macrophages M0 and NK cells resting were elevated in HNC tissues, while total T cells, total B cells, T cells CD8, B cell navie, T cell follicular helper, NK cells activated, Monocyte and Mast cells resting were decreased when compared to paracancerous tissues. Among each cell immune subtype, T cells regulatory Tregs, B cells naïve, T cells follicular helper, and T cells CD4 memory activated was significantly associated with HNC survival. Three clusters were observed via Cancer Subtypes R-package. Each cancer subtype has a specific molecular classification and subtype-specific immune cell characterization. Conclusions: Our data suggest a difference in immune response may be an important driver of HNC progression and response to treatment. The deconvolution algorithm of gene expression microarray data by CIBERSOFT provides useful information about the immune cell composition of HNC patients.

Dataset Information

Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression-based study.

Publications

Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression-based study.

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