The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2
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Published:2024-01-24
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ISSN:2662-1347
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Container-title:Nature Cancer
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language:en
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Short-container-title:Nat Cancer
Author:
Chaib SelimORCID, López-Domínguez José AlbertoORCID, Lalinde-Gutiérrez MartaORCID, Prats Neus, Marin Ines, Boix Olga, García-Garijo AndreaORCID, Meyer Kathleen, Muñoz María Isabel, Aguilera MònicaORCID, Mateo LidiaORCID, Stephan-Otto Attolini CamilleORCID, Llanos SusanaORCID, Pérez-Ramos SandraORCID, Escorihuela Marta, Al-Shahrour FatimaORCID, Cash Timothy P., Tchkonia TamaraORCID, Kirkland James L.ORCID, Abad MaríaORCID, Gros AlenaORCID, Arribas JoaquínORCID, Serrano ManuelORCID
Abstract
AbstractChemotherapy 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.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
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