The correlation between immune subtypes and consensus molecular subtypes in colorectal cancer identifies novel tumour microenvironment profiles, with prognostic and therapeutic implications

Soldevilla, Beatriz; Carretero-Puche, Carlos; Gómez‐López, Gonzalo; Al‐Shahrour, Fátima; Riesco, M.C.; Gil-Calderón, Beatriz; Álvarez‐Vallina, Luís; Espinosa-Olarte, Paula; Gomez-Esteves, G.; Rubio-Cuesta, Beatriz; Sarmentero, Jacinto; Salvia, Anna La; Garcia-Carbonero, Rocío

doi:10.1016/j.ejca.2019.09.008

Cited by 64 publications

(56 citation statements)

References 25 publications

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“…While NK cells were highly enriched in CMS1 tumours, increased fractions were also found in CMS3 tumours. Soldevilla et al also suggested that an inflammatory immune subtype was present in CMS3 as well as CMS4 tumours [35]. In line with previous findings, macrophages were found to be slightly enriched in CMS1 tumours and were mainly of HLA-DR + M1 type in this CMS subgroup.…”

Section: Discussionsupporting

confidence: 72%

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A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer

Ling

Kellgren

et al. 2020

Cancers

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The local anti-tumour immune response has important prognostic value in colorectal cancer (CRC). In the era of immunotherapy, a better understanding of the immune response in molecular subgroups of CRC may lead to significant advances in personalised medicine. On this note, microsatellite instable (MSI) tumours have been characterised by increased immune infiltration, suggesting MSI as a marker for immune inhibitor checkpoint therapy. Here, we used flow cytometry to perform a comprehensive analysis of immune activity profiles in tumour tissues, adjacent non-malignant tissues and blood, from a cohort of 69 CRC patients. We found several signs of immune suppression in tumours compared to adjacent non-malignant tissues, including T cells more often expressing the immune checkpoint molecules programmed cell death protein (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). We further analysed immune cell infiltration in molecular subgroups of CRC. MSI tumours were indeed found to be associated with increased immune infiltration, including increased fractions of PD-1+ T cells. No correlation was, however, found between MSI and the fraction of CTLA-4+ T cells. Interestingly, within the group of patients with microsatellite stable (MSS) tumours, some also presented with increased immune infiltration, including comparably high portions of PD-1+ T cells, but also CTLA-4+ T cells. Furthermore, no correlation was found between PD-1+ and CTLA-4+ T cells, suggesting that different tumours may, to some extent, be regulated by different immune checkpoints. We further evaluated the distribution of immune activity profiles in the consensus molecular subtypes of CRC. In conclusion, our findings suggest that different immune checkpoint inhibitors may be beneficial for selected CRC patients irrespective of MSI status. Improved predictive tools are required to identify these patients.

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Section: Discussionsupporting

confidence: 72%

“…The more comprehensive studies of immune infiltration in CRC have used transcriptomics to evaluate the immune response in different molecular subgroups of CRC, including the gold standard CMS subgroups [18,[33][34][35][36]. In brief, the four CRC CMS groups are shown to display relevant differences when it comes to immune infiltration.…”

Section: Discussionmentioning

confidence: 99%

A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer

Ling

Kellgren

et al. 2020

Cancers

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“…Soldevilla et al [ 63 ] evaluated the distribution of six immune subtypes proposed by Thorsson et al [ 64 ] among each CMS subtype in TCGA samples. In a total of 625 samples, the C1 wound healing subtype (77%) was the most predominant, followed by the C2 INF-γ dominant subtype (17%).…”

Section: Biomarkers Associated With Immune Microenvironment and Immunmentioning

confidence: 99%

Immune landscape and biomarkers for immuno-oncology in colorectal cancers

Bae

Yoo

Kim

et al. 2020

J Pathol Transl Med

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Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the third leading cause of cancer-related death in Korea [1]. Because of rapid spread of colonoscopy screening, there was a general decrease in CRC until 2010. However, recent studies have reported that the decline in CRC incidence has reversed during the last few years, especially in middle-aged persons, and the occurrence of early-onset CRC has rapidly increased [2]. Most patients with CRC are diagnosed at an operable stage; however, approximately 20% of patients with stage III or high-risk stage II CRC relapse within 5 years after curative resection [3]. Moreover, the 5-year relative survival rate for metastatic CRC is 14% [2]. To improve clinical outcomes for patients with CRC, a more effective treatment modality is required to fulfill those unmet needs. Cancer is fundamentally a genetic disease since the accumulation of mutations, fusions, and copy number alterations drives tumorigenesis. However, recent research on the tumor immune microenvironment (TIME) has revealed the importance of interactions between tumor cells and surrounding immune cells in tumorigenesis [4]. Immune checkpoint inhibitor (ICI) treatment , such as anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies and anti-programmed death-1 (PD-1) antibodies, has shown marked clinical benefits in many types of cancer [5,6]. CRC also holds promise for cancer immunotherapy use, and the U.S. Food and Drug Administration (U.S. FDA) approved immunotherapeutic agents for microsatellite instability-high (MSI-H) CRC in 2017 (Fig. 1) [7,8]. In this review, we describe the landscape of the immune microenvironment in CRC and summarize the clinical usefulness of several suggested biomarkers in CRC immunotherapy. IMMUNE LANDSCAPE OF COLORECTAL CANCERS Historical use of microscopic evaluation of immune environment in CRCs To our knowledge, Spratt and Spjut [9] published the first study on integrative histologic evaluation of CRCs in 1967. In that study, the authors evaluated histologic grade, mucinous elements, depth of invasion, characteristics of tumor border, lym

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“…CRC is the result of accumulated genetic, epigenetic, and endocrine aberrations [11,22]. The limitations of previous studies are that they focused on a single cohort study or results from a single database [23][24][25]. In the present study, we analyzed two microarray datasets GEO40967 and GEO8671 from GEO and RNA sequencing data form TCGA.…”

Section: Discussionmentioning

confidence: 99%

Identification of CXCL8 as an Immune Microenvironment Regulator of Colorectal Cancer: A Bioinformatics Study Based on Cancer Genome Atlas and Gene Expression Omnibus Datasets

Shao¹,

Gao²,

Cheng³

et al. 2020

Preprint

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BackgroundAt present, a lack of knowledge of the molecular mechanisms underlying the genesis and progression of colorectal cancer (CRC) exists. This is one of the reasons for poor prognosis of this increasingly occurring disease. The purpose of our research is to identify molecular candidates for therapeutic intervention that would help stop the malignant progression of CRC.MethodsIn this study, we performed bioinformatic analysis of the combined microarray data GSE40967 and GSE8671 in Gene Expression Omnibus (GEO) and the CRC RNA-seq dataset in The Cancer Genome Atlas (TCGA). This analysis consisted of 1067 CRC samples and 92 normal mucosae in total. We identified the common differentially expressed genes (DEGs) using R and Venn software. Protein–protein interaction (PPI) network information was obtained using the Search Tool for the Retrieval of Interacting Genes (STRING) Database. The Cytoscape plug-ins MCODE and cytoHubba were used to screen hub modules. CXCL8, which was the selected hub gene, was subjected to functional analysis and Gene Set Enrichment Analysis (GSEA). The algorithm “Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT)” was employed to estimate the relative abundance of tumor infiltrating lymphocyte cells (TILs) with CXCL8 expression. Finally, correlation analysis was carried out to explore the underlying mechanisms.ResultsWe identified 135 common DEGs, which consisted of 38 upregulated genes and 97 downregulated genes. The upregulated DEGs were strikingly enriched in regulation of neutrophil chemotaxis and cytokine-cytokine receptor interaction. The downregulated DEGs were enriched in bicarbonate transport. We identified the candidate molecule CXCL8 as a product of the hub gene. Functional enrichment analysis and GSEA indicated that CXCL8 may be closely related to a regulator of the CRC immune microenvironment. Finally, TILs analysis and correlation analysis showed that CXCL8 may inhibit CD8+ T cell immune infiltration through the HIF-1α/PD-Ls axis. In addition, CXCL8 could induce the polarization of M2 macrophages through the PI3K/AKT3 pathway.ConclusionsWe determined that hub gene CXCL8 may promote immune escape of CRC by inhibiting CD8+ T cell immune infiltration or promoting polarization of M2 macrophages. CXCL8 is a potential therapeutic target for the treatment of CRC patients.

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The correlation between immune subtypes and consensus molecular subtypes in colorectal cancer identifies novel tumour microenvironment profiles, with prognostic and therapeutic implications

Cited by 64 publications

References 25 publications

A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer

A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer

Immune landscape and biomarkers for immuno-oncology in colorectal cancers

Identification of CXCL8 as an Immune Microenvironment Regulator of Colorectal Cancer: A Bioinformatics Study Based on Cancer Genome Atlas and Gene Expression Omnibus Datasets

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