Prognostic and immunological roles of IL18RAP in human cancers

Across several cancers, IL18 receptor accessory protein (IL18RAP) is abnormally expressed, and this abnormality is related to tumor immunity and heterogeneous clinical outcomes. In this study, based on bioinformatics analysis, we discovered that IL18RAP is related to the human tumor microenvironment and promotes various immune cells infiltration. Additionally, the multiple immunofluorescence staining revealed that with the increased expression of IL18RAP, the number of infiltrated M1 macrophages increased. This finding was confirmed by coculture migration analysis using three human cancer cell lines (MDA-MB-231, U251, and HepG2) with IL18RAP knockdown. We discovered a positive link between IL18RAP and the majority of immunostimulators, immunoinhibitors, major histocompatibility complex (MHC) molecules, chemokines, and chemokine receptor genes using Spearman correlation analysis. Additionally, functional IL18RAP’s gene set enrichment analysis (GSEA) revealed that it is related to a variety of immunological processes, such as positive regulation of interferon gamma production and positive regulation of NK cell-mediated immunity. Moreover, we used single-cell RNA sequencing analysis to detect that IL18RAP was mainly expressed in immune cells, and HALLMARK analysis confirmed that the INF-γ gene set expression was upregulated in CD8Tex cells. In addition, in human and mouse cancer cohorts, we found that the level of IL18RAP can predict the immunotherapy response. In short, our study showed that IL18RAP is a new tumor biomarker and may become a potential immunotherapeutic target in cancer.

[1]  S. Salek-Ardakani,et al.  Reversing T-cell Exhaustion in Cancer: Lessons Learned from PD-1/PD-L1 Immune Checkpoint Blockade , 2021, Cancer Immunology Research.

[2]  G. Long,et al.  Immune checkpoint inhibitors in melanoma , 2021, The Lancet.

[3]  S. Salek-Ardakani,et al.  CD8+ T Cell Exhaustion in Cancer , 2021, Frontiers in Immunology.

[4]  T. Noda,et al.  Integrative genome‐wide analyses reveal the transcriptional aberrations in Japanese esophageal squamous cell carcinoma , 2021, Cancer science.

[5]  Liang Shi,et al.  An immunogenomic signature for molecular classification in hepatocellular carcinoma , 2021, Molecular therapy. Nucleic acids.

[6]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[7]  T. Meng,et al.  Identification and immunoprofiling of key prognostic genes in the tumor microenvironment of hepatocellular carcinoma , 2021, Bioengineered.

[8]  A. Jemal,et al.  Cancer Statistics, 2021 , 2021, CA: a cancer journal for clinicians.

[9]  R. Fernandes,et al.  Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors - A systematic review and meta-analysis. , 2020, Cancer treatment reviews.

[10]  E. Engleman,et al.  Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. , 2020, Annual review of pathology.

[11]  James M. McFarland,et al.  Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity , 2020, Nature Genetics.

[12]  Jeffrey S. Miller,et al.  Exploring the NK cell platform for cancer immunotherapy , 2020, Nature Reviews Clinical Oncology.

[13]  J. Barrett,et al.  Investigation of genetically regulated gene expression and response to treatment in rheumatoid arthritis highlights an association between IL18RAP expression and treatment response , 2020, Annals of the Rheumatic Diseases.

[14]  D. Lambrechts,et al.  A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling , 2020, Cell Research.

[15]  T. Schumacher,et al.  CD8+ T cell states in human cancer: insights from single-cell analysis , 2020, Nature Reviews Cancer.

[16]  J. D'haese,et al.  The role of interleukin-18 in pancreatitis and pancreatic cancer. , 2019, Cytokine & growth factor reviews.

[17]  M. Hung,et al.  Mechanisms Controlling PD-L1 Expression in Cancer. , 2019, Molecular cell.

[18]  L. Shevde,et al.  The Tumor Microenvironment Innately Modulates Cancer Progression. , 2019, Cancer research.

[19]  L. Galluzzi,et al.  Macrophages and Metabolism in the Tumor Microenvironment. , 2019, Cell metabolism.

[20]  E. Wherry,et al.  CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. , 2019, Annual review of immunology.

[21]  J. Pollard,et al.  Targeting macrophages: therapeutic approaches in cancer , 2018, Nature Reviews Drug Discovery.

[22]  P. L. Bergsagel,et al.  Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment. , 2018, Cancer cell.

[23]  Laurence Zitvogel,et al.  The immune contexture in cancer prognosis and treatment , 2017, Nature Reviews Clinical Oncology.

[24]  Hongyang Wang,et al.  Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes. , 2016, Cancer research.

[25]  H. Gu,et al.  Association of the interleukin-18 receptor 1 and interleukin-18 receptor accessory protein polymorphisms with the risk of esophageal cancer. , 2016, Biomedical reports.

[26]  R. Kefford,et al.  Immune checkpoint inhibitors in melanoma. , 2015, Melanoma management.

[27]  S. Scherer,et al.  A copy number variation map of the human genome , 2015, Nature Reviews Genetics.

[28]  Donatella,et al.  A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease , 2011, PLoS genetics.

[29]  D. Postma,et al.  Association of IL1RL1, IL18R1, and IL18RAP gene cluster polymorphisms with asthma and atopy. , 2008, The Journal of allergy and clinical immunology.

[30]  C. Dinarello,et al.  Clinical and experimental approaches to the pathophysiology of interleukin-18 in cancer progression , 2006, Cancer and Metastasis Reviews.

[31]  T. Ottenhoff,et al.  Divergent effects of IL‐12 and IL‐23 on the production of IL‐17 by human T cells , 2006, European journal of immunology.

[32]  Z. Cao,et al.  Accessory Protein-Like Is Essential for IL-18-Mediated Signaling1 , 2005, The Journal of Immunology.

[33]  A. Staiano,et al.  Interleukin 18 and associated markers of T helper cell type 1 activity in coeliac disease , 2002, Gut.

[34]  M. Taniguchi,et al.  IL-18 Enhances IL-4 Production by Ligand-Activated NKT Lymphocytes: A Pro-Th2 Effect of IL-18 Exerted Through NKT Cells1 , 2001, The Journal of Immunology.

[35]  I. Julkunen,et al.  IFN-α and IL-12 Induce IL-18 Receptor Gene Expression in Human NK and T Cells1 , 2000, The Journal of Immunology.

[36]  T. Born,et al.  Cloning of a Novel Receptor Subunit, AcPL, Required for Interleukin-18 Signaling* , 1998, The Journal of Biological Chemistry.

[37]  H. Okamura,et al.  Regulation of interferon-γ production by IL-12 and IL-18 , 1998 .

[38]  G. Fantuzzi,et al.  Overview of interleukin‐18: more than an interferon‐γ inducing factor , 1998, Journal of leukocyte biology.

[39]  S. Akira,et al.  Defective NK cell activity and Th1 response in IL-18-deficient mice. , 1998, Immunity.

[40]  H. Okamura,et al.  Cloning of a new cytokine that induces IFN-γ production by T cells , 1995, Nature.

[41]  N. Takahashi.  Aging , 1992, Cell.

[42]  C. Dinarello.  IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. , 1999, The Journal of allergy and clinical immunology.

[43]  H. Okamura,et al.  Regulation of interferon-gamma production by IL-12 and IL-18. , 1998, Current opinion in immunology.

[44]  H. Okamura,et al.  Cloning of a new cytokine that induces IFN-gamma production by T cells. , 1995, Nature.