Abstract
Immune checkpoint inhibitors (ICI) have emerged as an important therapeutic approach for patients with cancers including bladder cancer (BC). This commentary describes a recent study that demonstrated that the loss of Y chromosome (LOY) and/or loss of specific genes on Y chromosome confers an aggressive phenotype to BC because of T cell dysfunction resulting in CD8+T cell exhaustion. Loss of expression of Y chromosome genes KDM5D and UTY was similarly associated with an unfavorable prognosis in patients with BC as these genes were partially responsible for the impaired anti-tumor immunity in LOY tumors. From a clinical perspective, the study showed that tumors with LOY may be susceptible to treatment with ICIs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
All data and references mentioned in this manuscript are from publicly available sources. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
References
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
Wołącewicz M, Hrynkiewicz R, Grywalska E, et al. Immunotherapy in bladder cancer: current methods and future perspectives. Cancers (Basel). 2020;12(5):1181.
Semeniuk-Wojtaś A, Poddębniak-Strama K, Modzelewska M, et al. Tumour microenvironment as a predictive factor for immunotherapy in non-muscle-invasive bladder cancer. Cancer Immunol Immunother. 2023;72(7):1971–89.
Mishra V, Balasubramaniam G. Urinary bladder cancer and its associated factors–an epidemiological overview. Indian J Med Sci. 2021;73(2):239–48.
Abdel-Hafiz HA, Schafer JM, Chen X, et al. Y chromosome loss in cancer drives growth by evasion of adaptive immunity. Nature. 2023;619:624–31.
Powles T, Bellmunt J, Comperat E, et al. Bladder cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(3):244–58.
Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218–30.
Acuna-Hidalgo R, Veltman JA, Hoischen A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol. 2016;17:1–19.
Minner S, Kilgué A, Stahl P, et al. Y chromosome loss is a frequent early event in urothelial bladder cancer. Pathology. 2010;42(4):356–9.
Blair LP, Liu Z, Labitigan RLD, et al. KDM5 lysine demethylases are involved in maintenance of 3′ UTR length. Sci Adv. 2016;2(11):e1501662.
Li X, Liu L, Yang S, et al. Histone demethylase KDM5B is a key regulator of genome stability. Proc Natl Acad Sci. 2014;111(19):7096–101.
Zhu M, Zhang R-N, Zhang H, et al. PCGF6/MAX/KDM5D facilitates MAZ/CDK4 axis expression and pRCC progression by hypomethylation of the DNA promoter. Epigenetics Chromatin. 2023;16(1):9.
Patel R, Khalifa AO, Isali I, Shukla S. Prostate cancer susceptibility and growth linked to Y chromosome genes. Front Biosci (Elite Ed). 2018;10:423.
Hashimoto M, Kamphorst AO, Im SJ, et al. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu Rev Med. 2018;69:301–18.
Necchi A, Joseph RW, Loriot Y, et al. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: post-progression outcomes from the phase II IMvigor210 study. Ann Oncol. 2017;28(12):3044–50.
Santoni M, Myint ZW, Buttner T, et al. Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: the ARON-2 study. Cancer Immunol Immunother. 2023;72(9):2961–70.
Franklin MR, Platero S, Saini KS, Curigliano G, Anderson S. Immuno-oncology trends: preclinical models, biomarkers, and clinical development. J Immunother Cancer. 2022;10(1):e003231.
Salifu I, Singh N, Berraondo M, et al. Antibody-drug conjugates, immune-checkpoint inhibitors, and their combination in advanced non-small cell lung cancer. Cancer Treat Res Commun. 2023;36: 100713.
Saini KS, Punie K, Twelves C, et al. Antibody-drug conjugates, immune-checkpoint inhibitors, and their combination in breast cancer therapeutics. Expert Opin Biol Ther. 2021;21(7):945–62.
Authorship.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Funding
The funding of the study; the Rapid Service Fee and Open Access fee was funded by Fortrea.
Author information
Authors and Affiliations
Contributions
Arun K Mankan wrote the first draft of the manuscript, Begona de las Heras, Olga Bodriagova, Laura Vidal, Kamal S. Saini, Shakti H. Ramkissoon, Nagender Mankan, Enrique Grande provided significant intellectual input and reviewed, edited, and approved the final manuscript. All authors have reviewed the final version of this manuscript and provided their consent to publish.
Corresponding authors
Ethics declarations
Conflict of Interest
Arun K Mankan, Begona de las Heras, Olga Bodriagova, Laura Vidal, and Kamal S. Saini are employed by Fortrea Inc. Shakti H. Ramkissoon is employed by Labcorp Drug Development Inc. Nagender Mankan is employed by Northwest Georgia Oncology Centers, Roswell, Georgia, USA. Enrique Grande works at MD Anderson Cancer Center Madrid, Madrid, Spain. All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Kamal S Saini reports consulting fees from the European Commission, and stock and/or other ownership interests in Fortrea Inc. and Quantum Health Analytics (UK) Ltd., outside the submitted work. Enrique Grande has provided consulting/advisory services for MSD, Pfizer, Ipsen, Roche, Bristol-Myers Squibb, has received honoraria from Pfizer, Bristol-Myers Squibb, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Genzyme, Advanced Accelerator Applications, Novartis, Pierre Fabre, Lexicon, Celgene, Janssen-Cilag, Astellas Pharma, AstraZeneca, and Lilly, and has received travel/accommodations/expenses from Bristol-Myers Squibb, Roche/Genentech, Pfizer, Janssen-Cilag, and Ipsen and has received research funding from Roche, Pfizer, AstraZeneca, Ipsen, Molecular Templates, Lexicon, Astellas Pharma.
Ethical Approval
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Prior Presentation: This commentary is based on the article “Y chromosome loss in cancer drives growth by evasion of adaptive immunity” by Abel-Hafiz et al. The published article can be accessed at: https://doi.org/10.1038/s41586-023-06234-x.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Mankan, A.K., Mankan, N., de las Heras, B. et al. Bladder Cancer, Loss of Y Chromosome, and New Opportunities for Immunotherapy. Adv Ther 41, 885–890 (2024). https://doi.org/10.1007/s12325-023-02758-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12325-023-02758-w