Identification of Distinct Immune Subtypes in Colorectal Cancer Based on the Stromal Compartment

Shen, Rongfang; Li, Ping; Li, Bing; Zhang, Botao; Li, Feng; Cheng, Shujun

doi:10.3389/fonc.2019.01497

Cited by 40 publications

(34 citation statements)

References 67 publications

(54 reference statements)

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“…Additionally, there are various biological and clinical differences that may affect mutational characteristics and immune infiltration between different CRC locations (such as right-sided and left-sided CRCs) ( 47 ). Consistent with a previous study, our findings indicate that the TME and immune characteristics of MSI-H COAD might be somewhat different from those of MSI-H READ ( 48 ). For example, Shen et al revealed different molecular subtypes of CRC ( 48 ).…”

Section: Discussionsupporting

confidence: 90%

Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer

2020

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Colorectal cancer (CRC) patients, especially those with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors, whose sensitivity to immune checkpoint inhibitors (ICIs) is significantly higher than that of patients with microsatellite-stable (MSS)/microsatellite instability-low (MSI-L) tumors, have derived clinical benefits from immunotherapy. Most studies have not systematically evaluated the immune characteristics and immune microenvironments of MSI-H and MSS/MSI-L CRCs. We analyzed the relationship between the MSI status and prognosis of ICI treatment in an immunotherapy cohort. We further used mutation data for the immunotherapy and The Cancer Genome Atlas (TCGA)-CRC [colon adenocarcinoma (COAD) + rectum adenocarcinoma (READ)] cohorts. For mRNA expression, mutation data analysis of the immune microenvironment and immunogenicity under different MSI statuses was performed. Compared with CRC patients with MSS/MSI-L tumors, those with MSI-H tumors significantly benefited from ICI treatment. MSI-H CRC had more immune cell infiltration, higher expression of immune-related genes, and higher immunogenicity than MSS/MSI-L CRC. The MANTIS score, which is used to predict the MSI status, was positively correlated with immune cells, immune-related genes, and immunogenicity. In addition, subtype analysis showed that COAD and READ might have different immune microenvironments. MSI-H CRC may have an inflammatory tumor microenvironment and increased sensitivity to ICIs. Unlike those of MSI-H READ, the immune characteristics of MSI-H COAD may be consistent with those of MSI-H CRC.

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Section: Discussionsupporting

confidence: 90%

Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer

2020

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“…AMPKα2 has been found to impede the expression of FTO [19]. In this study, we first performed RT-qPCR and found an upregulation of FTO mRNA expression in CRC tissues and cells compared with the non-tumor tissues and HIEC cells ( Fig.…”

Section: Ampkα2 Impaired Crc Cell Proliferative Migratory and Invasimentioning

confidence: 77%

“…A minority of the CRC population are affected by the genetic mutations of oncogenes, anti-oncogenes or miRs [17][18][19]. Microarray profiling has identified a large range of miRNAs dysregulated in human CRC tissues, in contrast to adjacent non-cancerous tissues [20,21].…”

Section: Discussionmentioning

confidence: 99%

microRNA-96 promotes occurrence and progression of colorectal cancer via regulation of the AMPKα2-FTO-m6A/MYC axis

Yue

Chen

et al. 2020

J Exp Clin Cancer Res

100

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Background Colorectal cancer (CRC) is one of the frequently occurred malignancies in the world. To date, several onco-microRNAs (miRNAs or miRs), including miR-96, have been identified in the pathogenesis of CRC. In the present study, we aimed to corroborate the oncogenic effect of miR-96 on CRC and to identify the specific mechanisms related to AMPKα2/FTO/m6A/MYC. Methods RT-qPCR and Western blot analysis were performed to examine the expression pattern of miR-96, AMPKα2, FTO and MYC in the clinical CRC tissues and cells. The relationship between miR-96 and AMPKα2 was then predicted using in silico analysis and identified by dual-luciferase reporter assay. Gain- or loss-of-function approaches were manipulated to evaluate the modulatory effects of miR-96, AMPKα2, FTO and MYC on cell growth, cycle progression and apoptosis. The mechanism of FTO-mediated m6A modification of MYC was analyzed via Me-RIP and PAR-CLIP analysis. The mediatory effects of miR-96 antagomir on cancerogenesis were validated in vivo. Results miR-96, FTO and MYC were upregulated, while AMPKα2 was downregulated in CRC tissues and cells. miR-96 could down-regulate AMPKα2, which led to increased expression of FTO and subsequent upregulated expression of MYC via blocking its m6A modification. This mechanism was involved in the pro-proliferative and anti-apoptotic roles of miR-96 in CRC cells. Besides, down-regulation of miR-96 exerted inhibitory effect on tumor growth in vivo. Conclusions Taken together, miR-96 antagomir could potentially retard the cancerogenesis in CRC via AMPKα2-dependent inhibition of FTO and blocking FTO-mediated m6A modification of MYC, highlighting novel mechanisms associated with colorectal cancerogenesis.

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“…Furthermore, adequate tools are needed to stratify patients based on their TME [ 276 ]. General progress is being made, such as a pan-cancer immunogenomics study that distinguished six immune subtypes [ 277 ]; and recent work on subtyping patient with CRC, based on TME [ 278 , 279 , 280 ], may make clinical testing of new therapies more efficient. For example, (combinatorial) treatment strategies designed for a given TME subtype—that potentially could be present in different cancer types—would benefit from basket trials [ 281 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Combinatorial Immunotherapies for Metastatic Colorectal Cancer

Janssen

Subtil

Ortiz

et al. 2020

Cancers

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Colorectal cancer (CRC) is one of the most frequent and deadly forms of cancer. About half of patients are affected by metastasis, with the cancer spreading to e.g., liver, lungs or the peritoneum. The majority of these patients cannot be cured despite steady advances in treatment options. Immunotherapies are currently not widely applicable for this disease, yet show potential in preclinical models and clinical translation. The tumour microenvironment (TME) has emerged as a key factor in CRC metastasis, including by means of immune evasion—forming a major barrier to effective immuno-oncology. Several approaches are in development that aim to overcome the immunosuppressive environment and boost anti-tumour immunity. Among them are vaccination strategies, cellular transplantation therapies, and targeted treatments. Given the complexity of the system, we argue for rational design of combinatorial therapies and consider the implications of precision medicine in this context.

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Identification of Distinct Immune Subtypes in Colorectal Cancer Based on the Stromal Compartment

Cited by 40 publications

References 67 publications

Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer

Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer

microRNA-96 promotes occurrence and progression of colorectal cancer via regulation of the AMPKα2-FTO-m6A/MYC axis

Combinatorial Immunotherapies for Metastatic Colorectal Cancer

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