Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients

Liu, Jungang; Huang, Xiaoliang; Liu, Haizhou; Wei, Chunyin; Ru, Haiming; Qin, Haiquan; Lai, Hao; Meng, Yongsheng; Wu, Guan-Ling; Xie, Weishun; Mo, Xianwei; Johnson, Caroline H.; Zhang, Yawei; Tang, Weizhong

doi:10.1186/s12967-020-02638-9

Cited by 50 publications

(45 citation statements)

References 67 publications

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“…Moreover, some chemokine receptors have the potential to be drug targets in various diseases. 25 , 26 GIMAP7 is associated with the cytokine receptor interaction pathway, indicating its role in the induction of immune cell recruitment. Therefore, the intervention of GIMAP7 expression could impact the tumour immune microenvironment.…”

Section: Discussionmentioning

confidence: 99%

GIMAP7 as a Potential Predictive Marker for Pan-Cancer Prognosis and Immunotherapy Efficacy

Qin¹,

Li²,

Huang³

et al. 2022

JIR

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Background: GIMAP, a GTP enzyme of immune-related proteins, plays a crucial role in immune mechanisms. Investigating GIMAP7 expression in pan-cancer can provide efficient guidance for predicting clinical prognosis and identifying novel immunotherapy targets. Methods: Gene expression in different tumour types and stages was analysed based on The Cancer Genome Atlas and the Genotype-Tissue Expression database. An immunohistochemical assay was used to explore the differences in GIMAP7 protein levels in different tumour types and stages. Further, the cBioPortal was used to obtain the genetic variation characteristics of GIMAP7. Kaplan-Meier analysis and multivariable Cox regression analysis were performed to assess the prognostic value of GIMAP7. The pathways affected by GIMAP7 were studied based on gene set enrichment analysis, and the correlation between GIMAP7 expression and immune infiltration was determined using the TIMER2 database and the CIBERSORT method. ESTIMATE was used to analyse the correlation between GIMAP7 expression and ESTIMATE, immune and stromal scores. In addition, the correlation between GIMAP7 and immunoregulators was analysed. Furthermore, tumour mutational burden and microsatellite instability were evaluated using Spearman correlation assay. Results: GIMAP7 expression was significantly low and predicted better survival status in most tumour types. GIMAP7 was positively correlated with the abundance of CD8 + and CD4 + T cells in the tumour microenvironment. However, the high expression of GIMAP7 was negatively correlated with tumour mutations in uveal melanoma and colon adenocarcinoma. A correlation between GIMAP7 and microsatellite instability was found in rectal adenocarcinoma. Additionally, GIMAP7 presented a robust correlation between immune modulators and immunotherapeutic markers. Moreover, high GIMAP7 expression was significantly related to immune-relevant pathways. Conclusion:This study suggests the potential role of GIMAP7 as a prognostic and immunotherapeutic marker in pan-cancer, laying the groundwork for prospective functional and mechanistic experiments and their impact in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

GIMAP7 as a Potential Predictive Marker for Pan-Cancer Prognosis and Immunotherapy Efficacy

Qin¹,

Li²,

Huang³

et al. 2022

JIR

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“…However, most patients with CRC, except for those with high levels of microsatellite instability (MSI) or deficient mismatch repair (dMMR), cannot therapeutically benefit from immunotherapies because they have low immunogenicity [ 125 – 127 ]. Furthermore, recent studies have shown that KRAS -mutant CRC have significantly reduced infiltration of naïve B cells, macrophage M1, activated CD4 T cells, cytotoxic cells and neutrophils, and obviously increased regulatory T cells compared to patients with KRAS wild-type CRC [ 128 , 129 ]. Besides, multiple immune-related pathways are down-regulated in KRAS -mutant CRC, such as the interferon-γ (IFN-γ) pathway [ 129 ].…”

Section: Emerging Therapeuticsmentioning

confidence: 99%

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

et al. 2021

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Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

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“…For a reliable immune assessment, we used the TIMER algorithm to analyze immune scores and visualized them with the R “ggplot2” and “pheatmap” packages ( Newman et al, 2015 ; Becht et al, 2016 ; Li et al, 2016 ; Aran et al, 2017 ; Racle et al, 2017 ; Finotello et al, 2019 ; Sturm et al, 2019 ; Hu et al, 2020 ; Li et al, 2020 ; Liu et al, 2021 ). Next, we analyzed the infiltration of six immune cells using the TIMER 9 (tumor immune estimation resource) online tool.…”

Section: Methodsmentioning

confidence: 99%

Mapk14 is a Prognostic Biomarker and Correlates with the Clinicopathological Features and Immune Infiltration of Colorectal Cancer

Wang

Peng

et al. 2022

Front. Cell Dev. Biol.

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Background: Colorectal cancer (CRC) is one of the most common gastrointestinal tumors, ranking in the top 5 of all common tumors in terms of incidence and mortality. However, the mechanisms driving the evolution of colorectal cancer remain unclear. Therefore, we investigated the association between Mapk14 expression and clinicopathological and tumor-infiltrating immune cells.Methods: In this study, we collected CRC patient data from The Cancer Genome Atlas (TCGA), compared the expression level in CRC and normal colorectal tissue using the Wilcoxon rank sum test and assessed the relationship between Mapk14 and clinicopathological features using the Welch one-way ANOVA test. Kaplan-Meier and timeROC GSE17537 datasets were obtained from the Gene Expression Omnibus (GEO) dataset to assess the prognostic impact of the Mapk14 gene on colorectal cancer. Second, we further explored the methylation level of Mapk14 and its influencing factors. Single-cell sequencing of Mapk14 in the tumor immune microenvironment (TIME) was analyzed using the GSE108989 dataset. Further analyses based on the TIMER method were performed to assess the correlation between Mapk14 and tumor immune infiltration, immune checkpoints, tumor mutational load and microsatellite instability. Finally, the results of the bioinformatics analysis were verified by an immunohistochemical analysis.Results: The results showed that the expression of Mapk14 was upregulated in CRC tumor tissues compared with normal colorectal tissues and the high expression of Mapk14 was associated with poor clinicopathological features and poor prognoses in the CRC array. In addition, cg05798012 and cg25375420 of Mapk14 are the main DNA methylation sites affecting OS. Single-cell sequencing of the tumor immune microenvironment showed that the abundance and cell state of dysfunctional T cells changed greatly. Importantly, the abnormal overexpression of Mapk14 in colorectal cancer is related to the level of immune infiltration of immune cells (including CD8+ T cells, neutrophils, dendritic cells, B cells, CD4+ T cells, and macrophages). The high expression of Mapk14 was significantly correlated with immune checkpoints (including SIGLEC15, TIGIT, LAG3, CTLA4 and PDCDILG2), while the high expression of Mapk14 was negatively correlated with TMB and MSI but mostly positively correlated with drug sensitivity. Finally, the immunohistochemical results confirmed that the clinical stage (Ⅰ, Ⅱ, Ⅲ and Ⅳ) and M stage (M0 and M1) affected the abnormally high expression of Mapk14.Conclusion: A comprehensive bioinformatics study and experimental validation revealed that Mapk14 could serve as a novel prognostic biomarker associated with immune infiltration and pharmacotherapy and may represent a potential therapeutic target for the treatment of CRC.

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Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients

Cited by 50 publications

References 67 publications

GIMAP7 as a Potential Predictive Marker for Pan-Cancer Prognosis and Immunotherapy Efficacy

GIMAP7 as a Potential Predictive Marker for Pan-Cancer Prognosis and Immunotherapy Efficacy

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

Mapk14 is a Prognostic Biomarker and Correlates with the Clinicopathological Features and Immune Infiltration of Colorectal Cancer

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