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

Abstract

Chemotherapy; Intratumoral senescent cells

Quimioterapia; Células senescentes intratumorales

Quimioteràpia; Cèl·lules senescents intratumorals

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.

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).