Van Gulijk et al. addressed poorly understood mechanisms of resistance following anti-PD-1/PD-L1 therapy. In several solid tumor mouse models, ICB resistance correlated with preferentially enhanced Treg suppressive activity and Treg proliferation. Systemic Treg depletion reversed therapy-induced resistance, expanding effector T cells, and improving efficacy. ScRNA analysis of patient skin and lung tumor biopsies revealed Tregs from poor responders displayed an upregulated suppressive transcriptional gene program after ICB therapy. Treg activation was also observed in peripheral blood of ICB-non-responders with lung cancer and mesothelioma.
Contributed by Katherine Turner
ABSTRACT: Despite the clinical success of immune checkpoint blockade (ICB), in certain cancer types, most patients with cancer do not respond well. Furthermore, in patients for whom ICB is initially successful, this is often short-lived because of the development of resistance to ICB. The mechanisms underlying primary or secondary ICB resistance are incompletely understood. Here, we identified preferential activation and enhanced suppressive capacity of regulatory T cells (T(reg) cells) in αPD-L1 therapy-resistant solid tumor-bearing mice. T(reg) cell depletion reversed resistance to αPD-L1 with concomitant expansion of effector T cells. Moreover, we found that tumor-infiltrating T(reg) cells in human patients with skin cancer, and in patients with non-small cell lung cancer, up-regulated a suppressive transcriptional gene program after ICB treatment, which correlated with lack of treatment response. αPD-1/PD-L1-induced PD-1(+) T(reg) cell activation was also seen in peripheral blood of patients with lung cancer and mesothelioma, especially in nonresponders. Together, these data reveal that treatment with αPD-1 and αPD-L1 unleashes the immunosuppressive role of T(reg) cells, resulting in therapy resistance, suggesting that T(reg) cell targeting is an important adjunct strategy to enhance therapeutic efficacy.
Author Info: (1) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Erasmus MC Cancer Institute, Erasmus Medical Center Rotterdam, Rotterdam, Netherland
Author Info: (1) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Erasmus MC Cancer Institute, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (2) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Erasmus MC Cancer Institute, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (3) Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium. (4) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Erasmus MC Cancer Institute, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (5) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands. (6) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Erasmus MC Cancer Institute, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (7) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (8) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (9) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (10) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (11) Department of Biomics, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (12) JJP Biologics, Warsaw, Poland. (13) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. (14) Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. Institute for Chemical Immunology, Nijmegen, Netherlands. (15) Department of Dermatology, Leiden University Medical Center, Leiden, Netherlands. (16) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands. (17) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. (18) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Department of Cell Biology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (19) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Erasmus MC Cancer Institute, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (20) Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Erasmus MC Cancer Institute, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. (21) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands.
