Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

The Expression and Prognostic Value of Co-stimulatory Molecules in Clear Cell Renal Cell Carcinoma (CcRcc)

Author(s): Chengjiang Wu, Xiaojie Cai and Chunyan He*

Volume 27, Issue 2, 2024

Published on: 13 June, 2023

Page: [335 - 345] Pages: 11

DOI: 10.2174/1386207326666230511153724

Price: $65

Abstract

Background: Renal cell carcinoma (RCC) was one of the most common malignant cancers in the urinary system. Clear cell carcinoma (ccRCC) is the most common pathological type, accounting for approximately 80% of RCC. The lack of accurate and effective prognosis prediction methods has been a weak link in ccRCC treatment. Co-stimulatory molecules played the main role in increasing anti-tumor immune response, which determined the prognosis of patients. Therefore, the main objective of the present study was to explore the prognostic value of co-stimulatory molecules genes in ccRCC patients.

Methods: The TCGA database was used to get gene expression and clinical characteristics of patients with ccRCC. A total of 60 co-stimulatory molecule genes were also obtained from TCGAccRCC, including 13 genes of the B7/ CD28 co-stimulatory molecules family and 47 genes of the TNF family. In the TCGA cohort, the least absolute shrinkage and selection operator (LASSO) Cox regression model was used to generate a multigene signature. R and Perl programming languages were used for data processing and drawing. Real-time PCR was used to verify the expression of differentially expressed genes.

Results: The study's initial dataset included 539 ccRCC samples and 72 normal samples. The 13 samples have been eliminated. According to FDR<0.05, there were differences in the expression of 55 co-stimulatory molecule genes in ccRCC and normal tissues. LASSO Cox regression analysis results indicated that 13 risk genes were optimally used to construct a prognostic model of ccRCC. The patients were divided into a high-risk group and a low-risk group. Those in the high-risk group had significantly lower OS (Overall Survival rate) than patients in the low-risk group. Receiver operating characteristic (ROC) curve analysis confirmed the predictive value of the prognosis model of ccRCC (AUC>0.7). There are substantial differences in immune cell infiltration between high and low-risk groups. Functional analysis revealed that immune-related pathways were enriched, and immune status was different between the two risk groups. Real-time PCR results for genes were consistent with TCGA DEGs.

Conclusion: By stratifying patients with all independent risk factors, the prognostic score model developed in this study may improve the accuracy of prognosis prediction for patients with ccRCC.

Graphical Abstract

[1]
Sato, Y.; Yoshizato, T.; Shiraishi, Y.; Maekawa, S.; Okuno, Y.; Kamura, T.; Shimamura, T.; Sato-Otsubo, A.; Nagae, G.; Suzuki, H.; Nagata, Y.; Yoshida, K.; Kon, A.; Suzuki, Y.; Chiba, K.; Tanaka, H.; Niida, A.; Fujimoto, A.; Tsunoda, T.; Morikawa, T.; Maeda, D.; Kume, H.; Sugano, S.; Fukayama, M.; Aburatani, H.; Sanada, M.; Miyano, S.; Homma, Y.; Ogawa, S. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet., 2013, 45(8), 860-867.
[http://dx.doi.org/10.1038/ng.2699] [PMID: 23797736]
[2]
Serzan, M.T.; Atkins, M.B. Current and emerging therapies for first line treatment of metastatic clear cell renal cell carcinoma. J. Cancer Metastasis Treat., 2021, 7, 39.
[http://dx.doi.org/10.20517/2394-4722.2021.76] [PMID: 35295921]
[3]
Sanchez, D.J.; Simon, M.C. Genetic and metabolic hallmarks of clear cell renal cell carcinoma. Biochim. Biophys. Acta Rev. Cancer, 2018, 1870(1), 23-31.
[http://dx.doi.org/10.1016/j.bbcan.2018.06.003] [PMID: 29959988]
[4]
Cairns, P. Renal cell carcinoma. Cancer Biomark., 2011, 9(1-6), 461-473.
[http://dx.doi.org/10.3233/CBM-2011-0176] [PMID: 22112490]
[5]
Miller, K.D.; Nogueira, L.; Mariotto, A.B.; Rowland, J.H.; Yabroff, K.R.; Alfano, C.M.; Jemal, A.; Kramer, J.L.; Siegel, R.L. Cancer treatment and survivorship statistics, 2019. CA Cancer J. Clin., 2019, 69(5), 363-385.
[http://dx.doi.org/10.3322/caac.21565] [PMID: 31184787]
[6]
Vera-Badillo, F.E.; Templeton, A.J.; Duran, I.; Ocana, A.; de Gouveia, P.; Aneja, P.; Knox, J.J.; Tannock, I.F.; Escudier, B.; Amir, E. Systemic therapy for non-clear cell renal cell carcinomas: A systematic review and meta-analysis. Eur. Urol., 2015, 67(4), 740-749.
[http://dx.doi.org/10.1016/j.eururo.2014.05.010] [PMID: 24882670]
[7]
Herbst, R.S.; Baas, P.; Kim, D.W.; Felip, E.; Pérez-Gracia, J.L.; Han, J.Y.; Molina, J.; Kim, J.H.; Arvis, C.D.; Ahn, M.J.; Majem, M.; Fidler, M.J.; de Castro, G., Jr; Garrido, M.; Lubiniecki, G.M.; Shentu, Y. Im, E.; Dolled-Filhart, M.; Garon, E.B. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet, 2016, 387(10027), 1540-1550.
[http://dx.doi.org/10.1016/S0140-6736(15)01281-7] [PMID: 26712084]
[8]
Borghaei, H.; Paz-Ares, L.; Horn, L.; Spigel, D.R.; Steins, M.; Ready, N.E.; Chow, L.Q.; Vokes, E.E.; Felip, E.; Holgado, E.; Barlesi, F.; Kohlhäufl, M.; Arrieta, O.; Burgio, M.A.; Fayette, J.; Lena, H.; Poddubskaya, E.; Gerber, D.E.; Gettinger, S.N.; Rudin, C.M.; Rizvi, N.; Crinò, L.; Blumenschein, G.R., Jr; Antonia, S.J.; Dorange, C.; Harbison, C.T.; Graf Finckenstein, F.; Brahmer, J.R. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N. Engl. J. Med., 2015, 373(17), 1627-1639.
[http://dx.doi.org/10.1056/NEJMoa1507643] [PMID: 26412456]
[9]
Lou, Q.; Lü, M.; Yu, M. Anti-CD28 antibody costimulation enhances anti-CD3 antibody activating T cells and lowering TGF-beta expression in vitro. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2006, 14(3), 547-551.
[10]
Sanmamed, M.F.; Chen, L. A Paradigm Shift in Cancer Immunotherapy: From enhancement to normalization. Cell, 2019, 176(3), 677.
[http://dx.doi.org/10.1016/j.cell.2019.01.008] [PMID: 30682374]
[11]
Janakiram, M.; Chinai, J.M.; Zhao, A.; Sparano, J.A.; Zang, X. HHLA2 and TMIGD2: New immunotherapeutic targets of the B7 and CD28 families. OncoImmunology, 2015, 4(8), e1026534.
[http://dx.doi.org/10.1080/2162402X.2015.1026534]
[12]
Croft, M.; Benedict, C.A.; Ware, C.F. Clinical targeting of the TNF and TNFR superfamilies. Nat. Rev. Drug Discov., 2013, 12(2), 147-168.
[http://dx.doi.org/10.1038/nrd3930] [PMID: 23334208]
[13]
Gajewski, T.F.; Schreiber, H.; Fu, Y.X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol., 2013, 14(10), 1014-1022.
[http://dx.doi.org/10.1038/ni.2703] [PMID: 24048123]
[14]
Pan, Q.; Wang, L.; Chai, S.; Zhang, H.; Li, B. The immune infiltration in clear cell Renal Cell Carcinoma and their clinical implications: A study based on TCGA and GEO databases. J. Cancer, 2020, 11(11), 3207-3215.
[http://dx.doi.org/10.7150/jca.37285]
[15]
Christinat, Y.; Krek, W. Integrated genomic analysis identifies subclasses and prognosis signatures of kidney cancer. Oncotarget, 2015, 6(12), 10521-10531.
[http://dx.doi.org/10.18632/oncotarget.3294] [PMID: 25826081]
[16]
Leibler, C.; Thiolat, A.; Elsner, R.A.; El Karoui, K.; Samson, C.; Grimbert, P. Costimulatory blockade molecules and B-cell-mediated immune response: Current knowledge and perspectives. Kidney Int., 2019, 95(4), 774-786.
[http://dx.doi.org/10.1016/j.kint.2018.10.028] [PMID: 30711200]
[17]
So, T.; Ishii, N. The TNF-TNFR family of co-signal molecules. Adv. Exp. Med. Biol., 2019, 1189, 53-84.
[http://dx.doi.org/10.1007/978-981-32-9717-3_3] [PMID: 31758531]
[18]
Schorer, M.; Kuchroo, V.K.; Joller, N. Role of Co-stimulatory molecules in T helper cell differentiation. Adv. Exp. Med. Biol., 2019, 1189, 153-177.
[http://dx.doi.org/10.1007/978-981-32-9717-3_6] [PMID: 31758534]
[19]
Vecchiarelli, A. Cytokines and costimulatory molecules: Positive and negative regulation of the immune response to Cryptococcus neoformans. Arch. Immunol. Ther. Exp. (Warsz.), 2000, 48(6), 465-472.
[PMID: 11197600]
[20]
Kusztal, M.; Jezior, D.; Weyde, W. The immune response to kidney allograft. Part II: The role of costimulatory and accessory molecules in T-cell activation; the effector phase of response Postepy Hig. Med. Dosw., 2007, 61, 21-27.
[21]
Janakiram, M.; Shah, U.A.; Liu, W.; Zhao, A.; Schoenberg, M.P.; Zang, X. The third group of the B7- CD 28 immune checkpoint family: HHLA 2, TMIGD 2, B7x, and B7-H3. Immunol. Rev., 2017, 276(1), 26-39.
[http://dx.doi.org/10.1111/imr.12521] [PMID: 28258693]
[22]
Krummel, M.F.; Allison, J.P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med., 1995, 182(2), 459-465.
[http://dx.doi.org/10.1084/jem.182.2.459] [PMID: 7543139]
[23]
Watts, T.H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol., 2005, 23(1), 23-68.
[http://dx.doi.org/10.1146/annurev.immunol.23.021704.115839] [PMID: 15771565]
[24]
Croft, M. The TNF family in T cell differentiation and function - Unanswered questions and future directions. Semin. Immunol., 2014, 26(3), 183-190.
[http://dx.doi.org/10.1016/j.smim.2014.02.005] [PMID: 24613728]
[25]
Izda, V.; Jeffries, M.A.; Sawalha, A.H. COVID-19: A review of therapeutic strategies and vaccine candidates. Clin. Immunol., 2021, 222, 108634.
[http://dx.doi.org/10.1016/j.clim.2020.108634] [PMID: 33217545]
[26]
Cardona, G.; Rosselló, F.; Valiente, G. A perl package and an alignment tool for phylogenetic networks. BMC Bioinformatics, 2008, 9(175)
[http://dx.doi.org/10.1186/1471-2105-9-175]
[27]
Chan, B.K.C. Data analysis using r programming. Adv. Exp. Med. Biol., 2018, 1082, 47-122.
[http://dx.doi.org/10.1007/978-3-319-93791-5_2] [PMID: 30357717]
[28]
Ritchie, M.E.; Phipson, B.; Wu, D.; Hu, Y.; Law, C.W.; Shi, W.; Smyth, G.K. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res., 2015, 43(7), e47.
[http://dx.doi.org/10.1093/nar/gkv007] [PMID: 25605792]
[29]
Wang, R.; Zhu, Y.; Liu, X. The Clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer. BMC Cancer, 2019, 19, 1091.
[http://dx.doi.org/10.1186/s12885-019-6311-z]
[30]
Szklarczyk, D.; Gable, A.L.; Nastou, K.C.; Lyon, D.; Kirsch, R.; Pyysalo, S.; Doncheva, N.T.; Legeay, M.; Fang, T.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res., 2021, 49(D1), D605-D612.
[http://dx.doi.org/10.1093/nar/gkaa1074] [PMID: 33237311]
[31]
Qiu, H.; Hu, X.; He, C.; Yu, B.; Li, Y.; Li, J. Identification and validation of an individualized prognostic signature of bladder cancer based on seven immune related genes. Front. Genet., 2020, 11, 12.
[http://dx.doi.org/10.3389/fgene.2020.00012]
[32]
Wang, Q.; Wang, Z.; Li, G.; Zhang, C.; Bao, Z.; Wang, Z.; You, G.; Jiang, T. Identification of IDH-mutant gliomas by a prognostic signature according to gene expression profiling. Aging (Albany NY), 2018, 10(8), 1977-1988.
[http://dx.doi.org/10.18632/aging.101521] [PMID: 30115812]
[33]
Xiao, B.; Liu, L.; Li, A. Identification and Verification of Immune-Related Gene Prognostic Signature Based on ssGSEA for Osteosarcoma. Front. Oncol., 2020, 10, 607622.
[http://dx.doi.org/10.3389/fonc.2020.607622]
[34]
Zimpfer, A.; Glass, Ä.; Zettl, H.; Maruschke, M.; Hakenberg, O.W.; Erbersdobler, A. Renal cell carcinoma diagnosis and prognosis within the context of the WHO classification 2016. Urologe A, 2019, 58(9), 1057-1065.
[http://dx.doi.org/10.1007/s00120-019-0952-z] [PMID: 31093717]
[35]
Wu, C.; Cai, X.; Yan, J.; Deng, A.; Cao, Y.; Zhu, X. Identification of novel glycolysis-related gene signatures associated with prognosis of patients with clear cell renal cell carcinoma based on TCGA. Front. Genet., 2020, 11, 589663.
[http://dx.doi.org/10.3389/fgene.2020.589663]
[36]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)). Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy