The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and can result in complete remissions even at advanced stages of the disease. However, only a small fraction of patients respond to the treatment. To better understand which factors drive clinical benefit, we have generated whol...
| Autores: | , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universitat Pompeu Fabra |
| Repositorio: | Repositorio Digital de la UPF |
| OAI Identifier: | oai:repositori.upf.edu:10230/59600 |
| Acceso en línea: | http://hdl.handle.net/10230/59600 http://dx.doi.org/10.1038/s41598-023-42495-2 |
| Access Level: | acceso abierto |
| Palabra clave: | Cancer genomics Cancer immunotherapy Immunotherapy Urological cancer |
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The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancerBoll, Lilian MariePerera Bel, JúliaRodriguez-Vida, AlejoArpí Llucià, OriolRovira, AnaJuanpere, NuriaVázquez Montes de Oca, SergioHernández Llodrà, SilviaLloreta, Josep, 1958-Albà Soler, MarBellmunt Molins, Joaquim, 1959-Cancer genomicsCancer immunotherapyImmunotherapyUrological cancerImmune checkpoint inhibitors (ICI) have revolutionized cancer treatment and can result in complete remissions even at advanced stages of the disease. However, only a small fraction of patients respond to the treatment. To better understand which factors drive clinical benefit, we have generated whole exome and RNA sequencing data from 27 advanced urothelial carcinoma patients treated with anti-PD-(L)1 monoclonal antibodies. We assessed the influence on the response of non-synonymous mutations (tumor mutational burden or TMB), clonal and subclonal mutations, neoantigen load and various gene expression markers. We found that although TMB is significantly associated with response, this effect can be mostly explained by clonal mutations, present in all cancer cells. This trend was validated in an additional cohort. Additionally, we found that responders with few clonal mutations had abnormally high levels of T and B cell immune markers, suggesting that a high immune cell infiltration signature could be a better predictive biomarker for this subset of patients. Our results support the idea that highly clonal cancers are more likely to respond to ICI and suggest that non-additive effects of different signatures should be considered for predictive models.Nature Research202420242023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/59600http://dx.doi.org/10.1038/s41598-023-42495-2reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésSci Rep. 2023 Sep 15;13(1):15287© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/596002026-06-12T07:21:37Z |
| dc.title.none.fl_str_mv |
The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer |
| title |
The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer |
| spellingShingle |
The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer Boll, Lilian Marie Cancer genomics Cancer immunotherapy Immunotherapy Urological cancer |
| title_short |
The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer |
| title_full |
The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer |
| title_fullStr |
The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer |
| title_full_unstemmed |
The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer |
| title_sort |
The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer |
| dc.creator.none.fl_str_mv |
Boll, Lilian Marie Perera Bel, Júlia Rodriguez-Vida, Alejo Arpí Llucià, Oriol Rovira, Ana Juanpere, Nuria Vázquez Montes de Oca, Sergio Hernández Llodrà, Silvia Lloreta, Josep, 1958- Albà Soler, Mar Bellmunt Molins, Joaquim, 1959- |
| author |
Boll, Lilian Marie |
| author_facet |
Boll, Lilian Marie Perera Bel, Júlia Rodriguez-Vida, Alejo Arpí Llucià, Oriol Rovira, Ana Juanpere, Nuria Vázquez Montes de Oca, Sergio Hernández Llodrà, Silvia Lloreta, Josep, 1958- Albà Soler, Mar Bellmunt Molins, Joaquim, 1959- |
| author_role |
author |
| author2 |
Perera Bel, Júlia Rodriguez-Vida, Alejo Arpí Llucià, Oriol Rovira, Ana Juanpere, Nuria Vázquez Montes de Oca, Sergio Hernández Llodrà, Silvia Lloreta, Josep, 1958- Albà Soler, Mar Bellmunt Molins, Joaquim, 1959- |
| author2_role |
author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Cancer genomics Cancer immunotherapy Immunotherapy Urological cancer |
| topic |
Cancer genomics Cancer immunotherapy Immunotherapy Urological cancer |
| description |
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and can result in complete remissions even at advanced stages of the disease. However, only a small fraction of patients respond to the treatment. To better understand which factors drive clinical benefit, we have generated whole exome and RNA sequencing data from 27 advanced urothelial carcinoma patients treated with anti-PD-(L)1 monoclonal antibodies. We assessed the influence on the response of non-synonymous mutations (tumor mutational burden or TMB), clonal and subclonal mutations, neoantigen load and various gene expression markers. We found that although TMB is significantly associated with response, this effect can be mostly explained by clonal mutations, present in all cancer cells. This trend was validated in an additional cohort. Additionally, we found that responders with few clonal mutations had abnormally high levels of T and B cell immune markers, suggesting that a high immune cell infiltration signature could be a better predictive biomarker for this subset of patients. Our results support the idea that highly clonal cancers are more likely to respond to ICI and suggest that non-additive effects of different signatures should be considered for predictive models. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2024 2024 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10230/59600 http://dx.doi.org/10.1038/s41598-023-42495-2 |
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http://hdl.handle.net/10230/59600 http://dx.doi.org/10.1038/s41598-023-42495-2 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Sci Rep. 2023 Sep 15;13(1):15287 |
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http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf application/pdf |
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Nature Research |
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Nature Research |
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reponame:Repositorio Digital de la UPF instname:Universitat Pompeu Fabra |
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Universitat Pompeu Fabra |
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