IRF1 Inhibits Antitumor Immunity through the Upregulation of PD-L1 in the Tumor Cell

Shao, Lulu; Hou, Weizhou; Scharping, Nicole E.; Vendetti, Frank P.; Srivastava, Rashmi; Roy, Chandra Nath; Menk, Ashley V.; Wang, Yiyang; Chauvin, Joë-Marc; Karukonda, Pooja; Thorne, Stephen H.; Hornung, Veit; Zarour, Hassane M.; Bakkenist, Christopher J.; Delgoffe, Greg M.; Sarkar, Saumendra N.

doi:10.1158/2326-6066.cir-18-0711

Cited by 70 publications

(52 citation statements)

References 38 publications

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“…[ 43 ] A recent experiment reported that IRF1-deficient tumors exhibited enhanced cytotoxicity of CD8+ T cells through downregulation of PD-L1 expression. [ 44 ] The aforementioned results imply the presence of a mechanism to explain the limited efficacy of PD-1/PD-L1 checkpoint inhibitors. Further investigation is warranted to confirm this conjecture.…”

Section: Resultsmentioning

confidence: 99%

IRF1-mediated immune cell infiltration is associated with metastasis in colon adenocarcinoma

Shao

Wei

et al. 2020

Medicine

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Background: Evidence suggests that metastasis is chiefly responsible for the poor prognosis of colon adenocarcinoma (COAD). The tumor microenvironment plays a vital role in regulating this biological process. However, the mechanisms involved remain unclear. The aim of this study was to identify crucial metastasis-related biomarkers in the tumor microenvironment and investigate its association with tumor-infiltrating immune cells. Methods: We obtained gene expression profiles and clinical information from The Cancer Genome Atlas database. According to the “Estimation of STromal and Immune cells in MAlignant Tumor tissue using Expression data” algorithm, each sample generated the immune and stromal scores. Following correlation analysis, the metastasis-related gene was identified in The Cancer Genome Atlas database and validated in the GSE40967 dataset from Gene Expression Omnibus. The correlation between metastasis-related gene and infiltrating immune cells was assessed using the Tumor IMmune Estimation Resource database. Results: The analysis included 332 patients; the metastatic COAD samples showed a low immune score. Correlation analysis results showed that interferon regulatory factor 1 (IRF1) was associated with tumor stage, lymph node metastasis, and distant metastasis. Furthermore, significant associations between IRF1 and CD8+ T cells, T cell (general), dendritic cells, T-helper 1 cells, and T cell exhaustion were demonstrated by Spearmans correlation coefficients and P values. Conclusions: The present findings suggest that IRF1 is associated with metastasis and the degree of immune infiltration of CD8+ T cells (general), dendritic cells, T-helper 1 cells, and T cell exhaustion in COAD. These results may provide information for immunotherapy in colon cancer.

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Section: Resultsmentioning

confidence: 99%

IRF1-mediated immune cell infiltration is associated with metastasis in colon adenocarcinoma

Shao

Wei

et al. 2020

Medicine

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“…In parallel, the overexpression of the NOD-like receptor CARD domain-containing 5 (NLRC5) in melanoma cells enhances antitumor immunity by increasing the expression of MHC class I genes and presentation of tumor antigens [ 28 ]. Moreover, Irf1 , Ifitm3 , and Sp100 are involved in the interferon-mediated response that plays a role in antitumor immunity in melanoma [ 29 , 30 ]. DRAM1 (DNA damage-regulated autophagy modulator 1) and RTN1 (reticulon 1) are autophagy-inducing factors [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

et al. 2020

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Background: We have previously developed a murine cellular system that models the transformation from melanocytes to metastatic melanoma cells. This model was established by cycles of anchorage impediment of melanocytes and consists of four cell lines: differentiated melanocytes (melan-a), pre-malignant melanocytes (4C), malignant (4C11−), and metastasis-prone (4C11+) melanoma cells. Here, we searched for transcriptional and epigenetic signatures associated with melanoma progression and metastasis by performing a gene co-expression analysis of transcriptome data and a mass-spectrometry-based profiling of histone modifications in this model. Results: Eighteen modules of co-expressed genes were identified, and some of them were associated with melanoma progression, epithelial-to-mesenchymal transition (EMT), and metastasis. The genes in these modules participate in biological processes like focal adhesion, cell migration, extracellular matrix organization, endocytosis, cell cycle, DNA repair, protein ubiquitination, and autophagy. Modules and hub signatures related to EMT and metastasis (turquoise, green yellow, and yellow) were significantly enriched in genes associated to patient survival in two independent melanoma cohorts (TCGA and Leeds), suggesting they could be sources of novel prognostic biomarkers. Clusters of histone modifications were also linked to melanoma progression, EMT, and metastasis. Reduced levels of H4K5ac and H4K8ac marks were seen in the pre-malignant and tumorigenic cell lines, whereas the methylation patterns of H3K4, H3K56, and H4K20 were related to EMT. Moreover, the metastatic 4C11+ cell line showed higher H3K9me2 and H3K36me3 methylation, lower H3K18me1, H3K23me1, H3K79me2, and H3K36me2 marks and, in agreement, downregulation of the H3K36me2 methyltransferase Nsd1.

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“…Many studies reported that IRF1 is closely related to tumor inhibition. CD8 + T cells in IRF1-de cient melanoma showed increased cytotoxicity, the expression of PD-L1 was up-regulated, and tumor growth was more easily restored [32] . LAG3 is the third alternative inhibitory receptor targeted in tumor microenvironment, which has attracted much attention and research in clinical trials [33] .…”

Section: Discussionmentioning

confidence: 99%

Identification of Co-Expressed Genes Promoting CD8+ T Cell Infiltration in Melanoma Tumor Microenvironments

Yan

Wang

Xiao

2020

Preprint

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Purpose: To identify CD8+ T cell-related factors and the co-expression network in melanoma, to illustrate the interactions among CD8+ T cell-related genes in the melanoma tumor microenvironment.Method: We obtained melanoma and para-carcinoma tissue mRNA matrices from TCGA-SKCM and GSE65904. The CIBERSORT algorithm was used to assess CD8+ T cell proportions and the “estimate” package was used to assess melanoma tumor microenvironment purity. Weighted gene co-expression network analysis was used to identify the most related co-expression modules in TCGA-SKCM and GSE65904. Subsequently, a co-expression network was built based on the common results in the two cohorts. Results: Nine co-expressed genes (CCL5, GAP5, GZMA, GZMH, IRF1, LAG3, PRF1, NKG7, PSMB10) were identified as CD8+ T cell-related genes that promoted infiltration of CD8+ T cells, which were enriched in the cellular response to interferon−gamma process and antigen processing and presentation of peptide antigen. In the low expression level group, inflammation and immune responses were weaker, and the tumor purity was higher, suggesting that these genes were immune protective factors that improved the prognosis of melanoma. Besides this, co-expression factors negatively correlated with angiogenesis factors and positively correlated with angiogenesis inhibitors. Conclusion: These nine co-expressed genes promote high levels of infiltration of CD8+ T cells by the cellular response to the interferon−gamma process. The mechanism might provide new pathways for treatment of patients who are insensitive to PD-1 immunotherapy due to low degrees of CD8+ T cell infiltration.

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IRF1 Inhibits Antitumor Immunity through the Upregulation of PD-L1 in the Tumor Cell

Cited by 70 publications

References 38 publications

IRF1-mediated immune cell infiltration is associated with metastasis in colon adenocarcinoma

IRF1-mediated immune cell infiltration is associated with metastasis in colon adenocarcinoma

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

Identification of Co-Expressed Genes Promoting CD8+ T Cell Infiltration in Melanoma Tumor Microenvironments

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