Journal Article
. 2021 Jan; 158(1):1.
doi: 10.1186/s41065-020-00165-7.

Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes

Zihao Chen 1 Guojun Liu 2 Guoqing Liu 3 Mikhail A Bolkov 4 Khyber Shinwari 4 Irina A Tuzankina 4 Valery A Chereshnev 4 Zhifeng Wang 5 
  • PMID: 33388091
  •     54 References
  •     7 citations


Immunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA, RB1, FGFR3, KMT2C, MACF1, RYR2, and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.

Keywords: CD8+ T cells; Immunotherapy; Immunotype; MIBC; Molecular subtype; TMB.

TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
Sanjeev Mariathasan, Shannon J Turley, +39 authors, Thomas Powles.
Nature, 2018 Feb 15; 554(7693). PMID: 29443960    Free PMC article.
Highly Cited.
Bladder cancer stage-associated hub genes revealed by WGCNA co-expression network analysis.
Yu Di, Dongshan Chen, Wei Yu, Lei Yan.
Hereditas, 2019 Feb 07; 156. PMID: 30723390    Free PMC article.
Pan-Cancer Immunogenomic Perspective on the Tumor Microenvironment Based on PD-L1 and CD8 T-Cell Infiltration.
Chan-Young Ock, Bhumsuk Keam, +7 authors, Dae Seog Heo.
Clin Cancer Res, 2016 Jan 29; 22(9). PMID: 26819449
Highly Cited.
Three epigenetic biomarkers, GDF15, TMEFF2, and VIM, accurately predict bladder cancer from DNA-based analyses of urine samples.
Vera L Costa, Rui Henrique, +10 authors, Guro E Lind.
Clin Cancer Res, 2010 Oct 27; 16(23). PMID: 20975101
Molecular Pathways: Deciphering Mechanisms of Resistance to Macrophage-Targeted Therapies.
Daniela F Quail, Johanna A Joyce.
Clin Cancer Res, 2016 Nov 30; 23(4). PMID: 27895033    Free PMC article.
A co-expression network for differentially expressed genes in bladder cancer and a risk score model for predicting survival.
Zihao Chen, Guojun Liu, +5 authors, Wanlong Tan.
Hereditas, 2019 Jul 25; 156. PMID: 31333338    Free PMC article.
Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use.
Vipulkumar Dadhania, Miao Zhang, +13 authors, Bogdan Czerniak.
EBioMedicine, 2016 Oct 26; 12. PMID: 27612592    Free PMC article.
Highly Cited.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
Freddie Bray, Jacques Ferlay, +3 authors, Ahmedin Jemal.
CA Cancer J Clin, 2018 Sep 13; 68(6). PMID: 30207593
Highly Cited.
Identification of miR-200c and miR141-Mediated lncRNA-mRNA Crosstalks in Muscle-Invasive Bladder Cancer Subtypes.
Guojun Liu, Zihao Chen, +3 authors, Guoqing Liu.
Front Genet, 2018 Oct 17; 9. PMID: 30323832    Free PMC article.
The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy.
Jonathan J Havel, Diego Chowell, Timothy A Chan.
Nat Rev Cancer, 2019 Feb 14; 19(3). PMID: 30755690    Free PMC article.
Highly Cited. Review.
Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy.
Etienne Becht, Aurélien de Reyniès, +7 authors, Wolf Herman Fridman.
Clin Cancer Res, 2016 Mar 20; 22(16). PMID: 26994146
Highly Cited.
The future of immune checkpoint therapy.
Padmanee Sharma, James P Allison.
Science, 2015 Apr 04; 348(6230). PMID: 25838373
Highly Cited. Review.
Targeting CD8+ T-cell tolerance for cancer immunotherapy.
Stephanie R Jackson, Jinyun Yuan, Ryan M Teague.
Immunotherapy, 2014 Oct 08; 6(7). PMID: 25290416    Free PMC article.
A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments.
Kevin C Barry, Joy Hsu, +19 authors, Matthew F Krummel.
Nat Med, 2018 Jun 27; 24(8). PMID: 29942093    Free PMC article.
Highly Cited.
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.
Jonathan E Rosenberg, Jean Hoffman-Censits, +28 authors, Robert Dreicer.
Lancet, 2016 Mar 10; 387(10031). PMID: 26952546    Free PMC article.
Highly Cited.
Classifying Cancers Based on T-cell Infiltration and PD-L1.
Michele W L Teng, Shin Foong Ngiow, Antoni Ribas, Mark J Smyth.
Cancer Res, 2015 May 16; 75(11). PMID: 25977340    Free PMC article.
Highly Cited. Review.
Maftools: efficient and comprehensive analysis of somatic variants in cancer.
Anand Mayakonda, De-Chen Lin, +2 authors, H Phillip Koeffler.
Genome Res, 2018 Oct 21; 28(11). PMID: 30341162    Free PMC article.
Highly Cited.
Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial.
Padmanee Sharma, Margitta Retz, +16 authors, Matthew D Galsky.
Lancet Oncol, 2017 Jan 31; 18(3). PMID: 28131785
Highly Cited.
ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking.
Matthew D Wilkerson, D Neil Hayes.
Bioinformatics, 2010 Apr 30; 26(12). PMID: 20427518    Free PMC article.
Highly Cited.
clusterProfiler: an R package for comparing biological themes among gene clusters.
Guangchuang Yu, Li-Gen Wang, Yanyan Han, Qing-Yu He.
OMICS, 2012 Mar 30; 16(5). PMID: 22455463    Free PMC article.
Highly Cited.
Identification of SERPINE1, PLAU and ACTA1 as biomarkers of head and neck squamous cell carcinoma based on integrated bioinformatics analysis.
Ke Yang, Shizhou Zhang, +5 authors, Tengda Zhao.
Int J Clin Oncol, 2019 Apr 03; 24(9). PMID: 30937621    Free PMC article.
Identification of key pathways and genes in PTEN mutation prostate cancer by bioinformatics analysis.
Jian Sun, Shugen Li, +2 authors, Jianqing Wang.
BMC Med Genet, 2019 Dec 04; 20(1). PMID: 31791268    Free PMC article.
Recent Advances in Targeting CD8 T-Cell Immunity for More Effective Cancer Immunotherapy.
Aurélie Durgeau, Yasemin Virk, Stéphanie Corgnac, Fathia Mami-Chouaib.
Front Immunol, 2018 Feb 07; 9. PMID: 29403496    Free PMC article.
Highly Cited. Review.
The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors.
Andrew A Davis, Vaibhav G Patel.
J Immunother Cancer, 2019 Oct 28; 7(1). PMID: 31655605    Free PMC article.
Highly Cited.
Decorin: A Growth Factor Antagonist for Tumor Growth Inhibition.
Tero A H Järvinen, Stuart Prince.
Biomed Res Int, 2015 Dec 24; 2015. PMID: 26697491    Free PMC article.
Robust enumeration of cell subsets from tissue expression profiles.
Aaron M Newman, Chih Long Liu, +6 authors, Ash A Alizadeh.
Nat Methods, 2015 Mar 31; 12(5). PMID: 25822800    Free PMC article.
Highly Cited.
Molecular subtypes and response to immunotherapy in bladder cancer patients.
Tilman Todenhöfer, Roland Seiler.
Transl Androl Urol, 2019 Aug 09; 8(Suppl 3). PMID: 31392150    Free PMC article.
Re: Pooja Ghatalia, Matthew Zibelman, Daniel M. Geynisman, Elizabeth Plimack. Approved Checkpoint Inhibitors in Bladder Cancer: Which Drug Should Be Used When? Ther Adv Med Oncol 2018;10:1758835918788310: Knowing PD-L1 Status is Not Enough: Applying a Molecular Subtype Approach to Bladder Cancer is Also Needed.
Pontus Eriksson, Gottfrid Sjödahl, Fredrik Liedberg.
Eur Urol, 2018 Sep 29; 75(2). PMID: 30262340
Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.
Woonyoung Choi, Sima Porten, +17 authors, David J McConkey.
Cancer Cell, 2014 Feb 15; 25(2). PMID: 24525232    Free PMC article.
Highly Cited.
Loss of SPARC in bladder cancer enhances carcinogenesis and progression.
Neveen Said, Henry F Frierson, +2 authors, Dan Theodorescu.
J Clin Invest, 2013 Jan 17; 123(2). PMID: 23321672    Free PMC article.
Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.
Padmanee Sharma, Margaret K Callahan, +15 authors, Jonathan E Rosenberg.
Lancet Oncol, 2016 Oct 14; 17(11). PMID: 27733243    Free PMC article.
Highly Cited.
Coordination of intratumoral immune reaction and human colorectal cancer recurrence.
Matthieu Camus, Marie Tosolini, +10 authors, Jérôme Galon.
Cancer Res, 2009 Mar 05; 69(6). PMID: 19258510
A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization.
Miguel F Sanmamed, Lieping Chen.
Cell, 2018 Oct 06; 175(2). PMID: 30290139    Free PMC article.
Highly Cited. Review.
Tumor mutational burden (TMB) as a biomarker of response to immunotherapy in small cell lung cancer.
Yanis Boumber.
J Thorac Dis, 2018 Sep 21; 10(8). PMID: 30233840    Free PMC article.
Roles of SPARC in urothelial carcinogenesis, progression and metastasis.
Neveen Said.
Oncotarget, 2016 Aug 27; 7(41). PMID: 27564266    Free PMC article.
Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise.
Jaegil Kim, Rehan Akbani, +4 authors, David J Kwiatkowski.
Clin Cancer Res, 2015 Oct 17; 21(20). PMID: 26473186    Free PMC article.
Identification of key candidate genes and biological pathways in bladder cancer.
Xin Gao, Yinyi Chen, +3 authors, Shufang Zhang.
PeerJ, 2018 Dec 12; 6. PMID: 30533316    Free PMC article.
Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer--response.
Mario Sznol, Lieping Chen.
Clin Cancer Res, 2013 Sep 21; 19(19). PMID: 24048329    Free PMC article.
Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.
Razvan Cristescu, Robin Mogg, +21 authors, David Kaufman.
Science, 2018 Oct 13; 362(6411). PMID: 30309915    Free PMC article.
Highly Cited.
PD-1 blockade enhances the antitumor efficacy of GM-CSF surface-modified bladder cancer stem cells vaccine.
Xiaojun Shi, Xinji Zhang, +6 authors, Wanlong Tan.
Int J Cancer, 2017 Dec 16; 142(10). PMID: 29243219
New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype.
Jamie Lim, Neal M Poulin, Torsten O Nielsen.
Clin Cancer Res, 2015 Sep 04; 21(21). PMID: 26330427
Diagnosis of bladder cancer recurrence based on urinary levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 hypermethylation.
Thomas Reinert, Michael Borre, +3 authors, Lars Dyrskjøt.
PLoS One, 2012 Oct 12; 7(10). PMID: 23056278    Free PMC article.
Biomarkers for immunotherapy in bladder cancer: a moving target.
David H Aggen, Charles G Drake.
J Immunother Cancer, 2017 Nov 22; 5(1). PMID: 29157296    Free PMC article.
Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy.
Roland Seiler, Hussam Al Deen Ashab, +31 authors, Peter C Black.
Eur Urol, 2017 Apr 10; 72(4). PMID: 28390739
Highly Cited.
Analysis of the gene expression of SPARC and its prognostic value for bladder cancer.
M Yamanaka, K Kanda, +4 authors, S Kagawa.
J Urol, 2001 Nov 07; 166(6). PMID: 11696817
Biomarkers for Immunotherapy: Current Developments and Challenges.
Kristen R Spencer, Jianfeng Wang, +3 authors, Janice M Mehnert.
Am Soc Clin Oncol Educ Book, 2016 Jun 02; 35. PMID: 27249758
Mining TCGA database for tumor mutation burden and their clinical significance in bladder cancer.
Jia Lv, Yongze Zhu, +2 authors, Guodong Liao.
Biosci Rep, 2020 Apr 03; 40(4). PMID: 32239176    Free PMC article.
Approaches to treat immune hot, altered and cold tumours with combination immunotherapies.
Jérôme Galon, Daniela Bruni.
Nat Rev Drug Discov, 2019 Jan 06; 18(3). PMID: 30610226
Highly Cited. Review.
Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic.
T A Chan, M Yarchoan, +4 authors, S Peters.
Ann Oncol, 2018 Nov 06; 30(1). PMID: 30395155    Free PMC article.
Highly Cited. Review.
TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data.
Antonio Colaprico, Tiago C Silva, +10 authors, Houtan Noushmehr.
Nucleic Acids Res, 2015 Dec 26; 44(8). PMID: 26704973    Free PMC article.
Highly Cited.
Neoantigens in cancer immunotherapy.
Ton N Schumacher, Robert D Schreiber.
Science, 2015 Apr 04; 348(6230). PMID: 25838375
Highly Cited. Review.
Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis.
D Raggi, R Miceli, +5 authors, A Necchi.
Ann Oncol, 2015 Oct 22; 27(1). PMID: 26487582
Systematic Review.
WGCNA: an R package for weighted correlation network analysis.
Peter Langfelder, Steve Horvath.
BMC Bioinformatics, 2008 Dec 31; 9. PMID: 19114008    Free PMC article.
Highly Cited.
An essential role for decorin in bladder cancer invasiveness.
Mohamed El Behi, Sophie Krumeich, +13 authors, Clotilde Théry.
EMBO Mol Med, 2013 Oct 22; 5(12). PMID: 24142880    Free PMC article.
Prolonged Transcriptional Consequences in Survivors of Sepsis.
Krzysztof Laudanski, James Soh, Matthew DiMeglio, Kathleen E Sullivan.
Int J Mol Sci, 2021 Jun 03; 22(11). PMID: 34063857    Free PMC article.
Novel Therapies for Tongue Squamous Cell Carcinoma Patients with High-Grade Tumors.
Hao Lin, Lu Chen, Weizhong Li, Zihao Chen.
Life (Basel), 2021 Aug 28; 11(8). PMID: 34440557    Free PMC article.
A Machine Learning Model to Predict the Triple Negative Breast Cancer Immune Subtype.
Zihao Chen, Maoli Wang, +4 authors, Wenjie Shi.
Front Immunol, 2021 Oct 05; 12. PMID: 34603338    Free PMC article.
Development and Validation of a Gene Mutation-Associated Nomogram for Hepatocellular Carcinoma Patients From Four Countries.
Tingping Huang, Tao Yan, Gonghai Chen, Chunqing Zhang.
Front Genet, 2021 Oct 09; 12. PMID: 34621291    Free PMC article.
ISPRF: a machine learning model to predict the immune subtype of kidney cancer samples by four genes.
Zhifeng Wang, Zihao Chen, +5 authors, Degang Ding.
Transl Androl Urol, 2021 Nov 23; 10(10). PMID: 34804821    Free PMC article.
Prediction of Prognosis and Recurrence of Bladder Cancer by ECM-Related Genes.
Hongfan Zhao, Zihao Chen, +5 authors, Junfeng Zhao.
J Immunol Res, 2022 Apr 23; 2022. PMID: 35450397    Free PMC article.
Identification of Cancer-Associated Fibroblast Subtype of Triple-Negative Breast Cancer.
Maoli Wang, Ruifa Feng, +6 authors, Xiqing Li.
J Oncol, 2022 May 05; 2022. PMID: 35505821    Free PMC article.