Mitigating T cell DNA damage during PARP inhibitor treatment enhances antitumor efficacy
Menée à l'aide de modèles murins de tumeur et d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer épithélial de l'ovaire, cette étude démontre l'intérêt d'atténuer les dommages causés à l'ADN des lymphocytes T pour améliorer l'efficacité des inhibiteurs de PARP puis met en évidence l'efficacité antitumorale de lymphocytes CAR-T plus résistants à ces inhibiteurs
Poly(ADP-ribose) polymerase inhibitors (PARPis) are a class of agents targeting DNA damage repair that have become standard therapy for epithelial ovarian cancer (EOC) and multiple other solid tumors. In addition to targeting DNA damage repair, PARPis actively modulate antitumor immune responses, with efficacy being partially dependent on T cell activity. Here, we found that patient T cells sustain DNA damage during PARPi treatment, which reduces treatment efficacy. Leveraging paired pre- and posttreatment tumor samples from a clinical trial of patients with EOC treated with neoadjuvant niraparib as monotherapy, we showed that the PARPi caused DNA damage, slowed proliferation, and increased apoptosis in T cells, which we validated both in vitro and in mouse models. A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) knockout screen in primary human T cells identified PARP1 as the principal mediator of PARPi-induced T cell death. T cell–specific deletion of PARP1 or mutating Parp1 at its binding sites in transgenic mice led to reduced T cell DNA damage during PARPi treatment, resulting in improved efficacy of PARPis, alone or in combination with immune checkpoint inhibition. We then engineered PARPi-tolerant CAR T cells using cytosine base editing, which decreased PARPi-induced PARP1 trapping and led to reduced PARPi-induced DNA damage, resulting in superior antitumor efficacy in xenograft models compared with parental CAR T cells. This study highlights the relevance of PARPi-induced DNA damage to T cells and suggests opportunities to improve the efficacy of PARPis as monotherapy or in combination with immunotherapy. PARP inhibitors damage the DNA of T cells as well as tumor cells, and engineering CAR T cells to resist this damage improves treatment efficacy. In addition to targeting DNA damage repair, poly(ADP-ribose) polymerase (PARP) inhibitors modulate T cell activity to improve antitumor immunity. However, the combination of PARP inhibitors and immune checkpoint blockade (ICB) has achieved disappointing results in clinical trials. Here, Liu and colleagues identified that PARP inhibitors damaged the DNA of T cells in patients with epithelial ovarian carcinoma and identified PARP1 as key to this damage. Engineering T cell PARP1 to decrease PARP inhibitor–induced PARP1 trapping reduced endogenous or chimeric antigen receptor (CAR) T cell DNA damage and improved tumor responses to the combination of PARP inhibitors and ICB or CAR T cell therapy in mice. These results provide insight into clinical trial results and highlight opportunities to improve the efficacy of PARP inhibition. —Melissa L. Norton
Science Translational Medicine , article en libre accès 2025