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The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2 Chaib, S. López Domínguez, J. A. Lalinde Gutiérrez, M. Prats, Neus Marin, I. Boix, O. Garcia Garijo, A. Meyer, K. Muñoz, M. I. Aguilera, M. Mateo, L. Stephan Otto Attolini, C. Llanos, S. Pérez Ramos, S. Escorihuela, M. Al Shahrour, F. Cash, T. P. Tchkonia, T. Kirkland, J. L. Abad, María Gros, A. Arribas, J. Serrano, Manuel Quimioteràpia Cèl·lules canceroses Chemotherapy Cancer cells 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. © 2024, The Author(s). 2024-02-06T11:55:29Z 2024-02-06T11:55:29Z 2024-01-24 2024-02-05T16:30:26Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1038/s43018-023-00712-x Nature Cancer, 2024 https://doi.org/10.1038/s43018-023-00712-x cc by (c) Chaib, S. et al., 2024 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Nature Research Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))