Assessment for prognostic value of differentially expressed genes in immune microenvironment of clear cell renal cell carcinoma.

Tumor-infiltrating immune cells have been recognized to be associated with prognosis and response to immunotherapy; however, genes related to immune microenvironment of clear cell renal cell carcinoma (ccRCC) remains unclear. To better understand the effects of genes involved in immune and stromal cells on prognosis, we used Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC), DAVID database and ESTMATE algorithm, and divided the patients into low and high groups according to immune (median: 1038.45) and stromal scores (median: 667.945), respectively. We found the immune scores were significantly correlated with clinicopathological parameters and overall survival (OS). Based on immune scores, 890 DEGs were significantly associated with OS among the 1433 up-regulated genes. Based on top 10 DEGs (IL10RA, FCER1G, SASH3, TIGIT, RHOH, IL12RB1, AIF1, LPXN, LAPTM5 and SP140), cases with number of up-regulated genes ≥ 5 were associated poor OS (P = 0.002). In addition, the mean differences of percentages of CD8 T cells (11.32%), CD4 memory resting T cells (-4.52%) and mast resting cells (-3.55%) between low and high immune scores were the most significant. Thus, combination of these genes might use to predict the efficacy of immunotherapy. Further analyses of these genes were warrant to explore their potential association with the prognosis of ccRCC.

[1]  D. Ye,et al.  Prognostic value and immune infiltration of novel signatures in clear cell renal cell carcinoma microenvironment , 2019, Aging.

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

[3]  Lei Gao,et al.  TIGIT expression is upregulated in T cells and causes T cell dysfunction independent of PD-1 and Tim-3 in adult B lineage acute lymphoblastic leukemia. , 2019, Cellular immunology.

[4]  W. Linehan,et al.  The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications , 2019, Nature Reviews Urology.

[5]  C. Voena,et al.  RHO Family GTPases in the Biology of Lymphoma , 2019, Cells.

[6]  J. Manola,et al.  Predicting Renal Cancer Recurrence: Defining Limitations of Existing Prognostic Models With Prospective Trial-Based Validation. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  T. Powles,et al.  Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal‐Cell Carcinoma , 2019, The New England journal of medicine.

[8]  R. Motzer,et al.  Avelumab plus Axitinib versus Sunitinib for Advanced Renal‐Cell Carcinoma , 2019, The New England journal of medicine.

[9]  W. Xue,et al.  Integrated analysis of dysregulated long non-coding RNAs/microRNAs/mRNAs in metastasis of lung adenocarcinoma , 2018, Journal of Translational Medicine.

[10]  Víctor Potenciano,et al.  SP140 regulates the expression of immune‐related genes associated with multiple sclerosis and other autoimmune diseases by NF‐&kgr;B inhibition , 2018, Human molecular genetics.

[11]  Lijie Zhou,et al.  Leupaxin Promotes Bladder Cancer Proliferation, Metastasis, and Angiogenesis Through the PI3K/AKT Pathway , 2018, Cellular Physiology and Biochemistry.

[12]  Mingbo Zhao,et al.  Identification of potential crucial genes associated with carcinogenesis of clear cell renal cell carcinoma , 2018, Journal of cellular biochemistry.

[13]  J. Reeves,et al.  Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma , 2018, Nature Medicine.

[14]  J. Larkin,et al.  Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427. , 2018 .

[15]  Guanming Wu,et al.  Network-Based Predictors of Progression in Head and Neck Squamous Cell Carcinoma , 2018, Front. Genet..

[16]  F. Marincola,et al.  International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study , 2018, The Lancet.

[17]  Bohuslav Melichar,et al.  Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal‐Cell Carcinoma , 2018, The New England journal of medicine.

[18]  V. Margulis,et al.  The Rho GTPase signalling pathway in urothelial carcinoma , 2018, Nature Reviews Urology.

[19]  I. Wistuba,et al.  Programmed cell death ligand 1 and tumor‐infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation , 2017, Cancer.

[20]  Xinghuan Wang,et al.  Co-expression network analysis identified FCER1G in association with progression and prognosis in human clear cell renal cell carcinoma , 2017, International journal of biological sciences.

[21]  Ying Sun,et al.  Genomic Analysis of Tumor Microenvironment Immune Types across 14 Solid Cancer Types: Immunotherapeutic Implications , 2017, Theranostics.

[22]  Nicolai J. Birkbak,et al.  Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. , 2017, The Lancet. Oncology.

[23]  M. Atkins,et al.  Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions. , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  Anna C. Salzberg,et al.  RNA-seq implicates deregulation of the immune system in the pathogenesis of diverticulitis. , 2017, American journal of physiology. Gastrointestinal and liver physiology.

[25]  Michael B. Stadler,et al.  An Immune Atlas of Clear Cell Renal Cell Carcinoma , 2017, Cell.

[26]  M. Hou,et al.  TIGIT, A Novel Therapeutic Target for Tumor Immunotherapy , 2017, Immunological investigations.

[27]  S. Sakaguchi,et al.  Regulatory T cells in cancer immunotherapy , 2016, Cell Research.

[28]  Ludmila V. Danilova,et al.  Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures , 2016, Genome Biology.

[29]  P. Ross-Macdonald,et al.  Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma , 2016, Clinical Cancer Research.

[30]  L. Zitvogel,et al.  Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[31]  A. Ravaud,et al.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. , 2015, The New England journal of medicine.

[32]  Matteo Brunelli,et al.  Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers , 2015, PloS one.

[33]  A. Jukkola-Vuorinen,et al.  Tumor infiltrating CD8+ T lymphocyte count is independent of tumor TLR9 status in treatment naïve triple negative breast cancer and renal cell carcinoma , 2015, Oncoimmunology.

[34]  R. Motzer,et al.  Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  P. Burfeind,et al.  Leupaxin stimulates adhesion and migration of prostate cancer cells through modulation of the phosphorylation status of the actin-binding protein caldesmon , 2015, Oncotarget.

[36]  P. Sharma,et al.  The future of immune checkpoint therapy , 2015, Science.

[37]  Ash A. Alizadeh,et al.  Robust enumeration of cell subsets from tissue expression profiles , 2015, Nature Methods.

[38]  A. Sacchetti,et al.  Tumor-specific mutations in low-frequency genes affect their functional properties , 2015, Journal of Neuro-Oncology.

[39]  R. Robinson IL12Rβ1: the cytokine receptor that we used to know. , 2015, Cytokine.

[40]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[41]  N. Hacohen,et al.  Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity , 2015, Cell.

[42]  H. Kohrt,et al.  Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients , 2014, Nature.

[43]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[44]  Jeffrey W Pollard,et al.  Tumor-associated macrophages: from mechanisms to therapy. , 2014, Immunity.

[45]  G. Getz,et al.  Inferring tumour purity and stromal and immune cell admixture from expression data , 2013, Nature Communications.

[46]  H. Schreiber,et al.  Innate and adaptive immune cells in the tumor microenvironment , 2013, Nature Immunology.

[47]  David A. Williams,et al.  Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders. , 2013, Experimental cell research.

[48]  D. Miranda-Saavedra,et al.  The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges , 2013, Briefings in functional genomics.

[49]  Zheng-wang Chen,et al.  Role of AIF-1 in the regulation of inflammatory activation and diverse disease processes. , 2013, Cellular immunology.

[50]  M. Harrison,et al.  Novel immunotherapeutic strategies in development for renal cell carcinoma. , 2013, European urology.

[51]  S. Poletajew,et al.  Spontaneous regression of renal cell carcinoma , 2013, Contemporary oncology.

[52]  A. McKenna,et al.  Absolute quantification of somatic DNA alterations in human cancer , 2012, Nature Biotechnology.

[53]  Douglas Hanahan,et al.  Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment Prospects and Obstacles for Therapeutic Targeting of Function-enabling Stromal Cell Types , 2022 .

[54]  K. Shimada,et al.  Prognostic significance of CD45RO+ memory T cells in renal cell carcinoma , 2011, British Journal of Cancer.

[55]  Luigi Naldini,et al.  FcRgamma activation regulates inflammation-associated squamous carcinogenesis. , 2010, Cancer cell.

[56]  Zlatko Trajanoski,et al.  In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  J. Cheville,et al.  PD-1 Is Expressed by Tumor-Infiltrating Immune Cells and Is Associated with Poor Outcome for Patients with Renal Cell Carcinoma , 2007, Clinical Cancer Research.

[58]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[59]  M. Atkins,et al.  Update on the Role of Interleukin 2 and Other Cytokines in the Treatment of Patients with Stage IV Renal Carcinoma , 2004, Clinical Cancer Research.

[60]  D. McMillan,et al.  The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer , 2003, British Journal of Cancer.

[61]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[62]  H Nagura,et al.  Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. , 2001, Cancer research.

[63]  H. Takayama,et al.  A Novel Association of Fc Receptor γ-Chain with Glycoprotein VI and Their Co-expression as a Collagen Receptor in Human Platelets* , 1997, The Journal of Biological Chemistry.

[64]  Yi Luo,et al.  Downregulation of LAPTM5 suppresses cell proliferation and viability inducing cell cycle arrest at G0/G1 phase of bladder cancer cells. , 2017, International journal of oncology.

[65]  C. Klein,et al.  Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans. , 2014, Advances in immunology.

[66]  Steven A. Roberts,et al.  Mutational heterogeneity in cancer and the search for new cancer-associated genes , 2013 .

[67]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[68]  M. Karno,et al.  Renal cell carcinoma. , 1956, Bulletin. Tufts-New England Medical Center.