| First Author | Obradovic A | Year | 2023 |
| Journal | Cancer Cell | Volume | 41 |
| Issue | 5 | Pages | 933-949.e11 |
| PubMed ID | 37116491 | Mgi Jnum | J:337319 |
| Mgi Id | MGI:7487864 | Doi | 10.1016/j.ccell.2023.04.003 |
| Citation | Obradovic A, et al. (2023) Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators. Cancer Cell 41(5):933-949.e11 |
| abstractText | Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive immuno-oncology targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate master regulators (MRs) as mechanistic determinants of TI-Treg transcriptional state. Pooled CRISPR-Cas9 screening in vivo, using a chimeric hematopoietic stem cell transplant model, confirmed the essentiality of eight MRs in TI-Treg recruitment and/or retention without affecting other T cell subtypes, and targeting one of the most significant MRs (Trps1) by CRISPR KO significantly reduced ectopic tumor growth. Analysis of drugs capable of inverting TI-Treg MR activity identified low-dose gemcitabine as the top prediction. Indeed, gemcitabine treatment inhibited tumor growth in immunocompetent but not immunocompromised allografts, increased anti-PD-1 efficacy, and depleted MR-expressing TI-Tregs in vivo. This study provides key insight into Treg signaling, specifically in the context of cancer, and a generalizable strategy to systematically elucidate and target MR proteins in immunosuppressive subpopulations. |
