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Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators.

Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators. Cancer cell Obradovic, A., Ager, C., Turunen, M., Nirschl, T., Khosravi-Maharlooei, M., Iuga, A., Jackson, C. M., Yegnasubramanian, S., Tomassoni, L., Fernandez, E. C., McCann, P., Rogava, M., DeMarzo, A. M., Kochel, C. M., Allaf, M., Bivalacqua, T., Lim, M., Realubit, R., Karan, C., Drake, C. G., Califano, A. 2023

Abstract

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.

View details for DOI 10.1016/j.ccell.2023.04.003

View details for PubMedID 37116491