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

Aleksandar Obradovic, Casey Ager, Mikko Turunen, Thomas Nirschl, Mohsen Khosravi-Maharlooei, Alina Iuga, Christopher M. Jackson, Srinivasan Yegnasubramanian, Lorenzo Tomassoni, Ester Calvo Fernandez, Patrick McCann, Meri Rogava, Angelo M. DeMarzo, Christina M. Kochel, Mohamad Allaf, Trinity Bivalacqua, Michael Lim, Ronald Realubit, Charles Karan, Charles G. DrakeAndrea Califano

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)933-949.e11
JournalCancer cell
Volume41
Issue number5
DOIs
StatePublished - May 8 2023

Keywords

  • TRPS1
  • cancer systems biology
  • gemcitabine
  • master regulator analysis
  • regulatory T cells
  • tumor immunology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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