Chaib and López-Domínguez et al. demonstrated that senescence-inducing therapies upregulated PD-L2 upon induction of senescence in different cancer cells. However, PD-L2 was not necessary for senescence induction or for the secretory phenotype of senescent cells, but it was critical for cells to evade the immune system and persist intratumorally. PD-L2-deficient tumor cells were rapidly eliminated by CD8+ T cells, did not secrete the senescence-associated chemokines CXCL1 and CXCL2, and failed to recruit myeloid-derived suppressor cells. Antibody-mediated PD-L2 blockade synergized with chemotherapy to improve immune surveillance.
Contributed by Shishir Pant
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.
Author Info: (1) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Author Info: (1) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA. (2) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. josealberto.lopez@irbbarcelona.org. (3) Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. (4) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. (5) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. Genentech, South San Francisco, CA, USA. (6) Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. (7) Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. (8) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. Cambridge Institute of Science, Altos Labs, Cambridge, UK. (9) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. (10) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. (11) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. (12) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. (13) DNA Replication Group, Spanish National Cancer Research Center, Madrid, Spain. (14) Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. (15) Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. (16) Bioinformatics Unit, Spanish National Cancer Research Center, Madrid, Spain. (17) Rejuveron Senescence Therapeutics, Zrich, Switzerland. (18) Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. (19) Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. (20) Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Cambridge Institute of Science, Altos Labs, Cambridge, UK. (21) Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. (22) Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Cancer Research Program, Hospital del Mar Medical Research Institute, Centro de Investigacin Biomdica en Red Cncer, Barcelona, Spain. Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Instituci Catalana de Recerca i Estudis Avanats, Barcelona, Spain. (23) Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. mserrano@altoslabs.com. Cambridge Institute of Science, Altos Labs, Cambridge, UK. mserrano@altoslabs.com. Instituci Catalana de Recerca i Estudis Avanats, Barcelona, Spain. mserrano@altoslabs.com.
