The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2

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• dc.contributor.author Chaib, Selim
• dc.contributor.author Arribas, Joaquín
• dc.contributor.author Serrano, Manuel
• dc.date.accessioned 2024-10-29T07:27:51Z
• dc.date.available 2024-10-29T07:27:51Z
• dc.date.issued 2024
• dc.description.abstract Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence.
• dc.description.sponsorship We thank the IRB Core Facilities (Functional Genomics Core, Biostatistics/Bioinformatics and Histopathology), the Parc Científic de Barcelona Animal Facility and the University of Barcelona/Centros Científicos y Tecnológicos de la Universidad de Barcelona Flow Cytometry Facility for their contribution to this work. J.A.L-D. was supported by the Spanish Ministry of Science through a Juan de la Cierva-Incorporación fellowship and by the Asociación Española Contra el Cáncer (AECC) through an AECC Investigador fellowship. I.M. was funded by an FPI fellowship from the Spanish Ministry of Science. Work in the laboratory of M.S. was funded by the IRB and ‘la Caixa’ Foundation, and by grants from the Spanish Ministry of Science cofunded by the European Regional Development Fund (ERDF) (no. SAF2017-82613-R), European Research Council (no. ERC-2014-AdG/669622) and Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282). J.L.K., T.T. and S.C. were supported by the National Institutes of Health (grant nos. R37AG13925, R33AG61456, R01AG072301, R01AG61414, P01AG62413 and UH3AG56933), the Connor Fund, Robert J. and Theresa W. Ryan and the Noaber Foundation. A.G. received funding from the Spanish Ministry of Science cofunded by the ERDF (no. RTC-2017-6123-1), from the Instituto de Salud Carlos III (no. MS15/00058) and from CAIMI-II (grant no. 53/2021) supported by the BBVA Foundation. A.G.-G. was the recipient of a PERIS grant (no. SLT017/20/000131) from the Generalitat de Catalunya. The laboratory of M. Abad received funding from the Spanish Ministry of Science and Innovation (nos. RTI2018-102046-B-I00A and RTC-2017-6123-1) and the AECC (no. PRYCO211023SERR). M.A. was the recipient of a Ramón y Cajal contract from the Spanish Ministry of Science and Innovation (no. RYC-2013-14747). O.B. was the recipient of a FPIAGAUR fellowship from Generalitat de Catalunya. Work in the laboratory of J.A. is supported by the Breast Cancer Research Foundation (no. BCRF-21-008), Instituto de Salud Carlos III (project refs. AC15/00062, CB16/12/00449 and PI19/01181) and the European Commission (under the Framework of the ERA-NET TRANSCAN-2 initiative cofinanced by FEDER), AECC and Fundació La Caixa (no. HR22-00776).
• dc.format.mimetype application/pdf
• dc.identifier.citation Chaib S, López-Domínguez JA, Lalinde-Gutiérrez M, Prats N, Marin I, Boix O, et al. The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2. Nat Cancer. 2024 Mar;5(3):448-62. DOI: 10.1038/s43018-023-00712-x
• dc.identifier.doi http://dx.doi.org/10.1038/s43018-023-00712-x
• dc.identifier.issn 2662-1347
• dc.identifier.uri http://hdl.handle.net/10230/68382
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Cancer. 2024 Mar;5(3):448-62
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/669622
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-82613-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-102046-B-I00A
• dc.rights © The Author(s) 2024. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cancer
• dc.subject.keyword Senescence
• dc.title The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion