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 Drake; Andrea Califano

doi:10.1016/j.ccell.2023.04.003

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

Cancer Cell. 2023 May 8;41(5):933-949.e11. doi: 10.1016/j.ccell.2023.04.003. Epub 2023 Apr 27.

Authors

Aleksandar Obradovic¹, Casey Ager², Mikko Turunen³, Thomas Nirschl⁴, Mohsen Khosravi-Maharlooei⁵, Alina Iuga⁶, Christopher M Jackson⁷, Srinivasan Yegnasubramanian⁴, Lorenzo Tomassoni³, Ester Calvo Fernandez³, Patrick McCann⁸, Meri Rogava⁸, Angelo M DeMarzo⁹, Christina M Kochel⁴, Mohamad Allaf¹⁰, Trinity Bivalacqua¹⁰, Michael Lim¹¹, Ronald Realubit¹², Charles Karan¹², Charles G Drake¹³, Andrea Califano¹⁴

Affiliations

¹ Columbia Center for Translational Immunology, Irving Medical Center, New York, NY, USA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
² Columbia Center for Translational Immunology, Irving Medical Center, New York, NY, USA; Department of Hematology Oncology, Columbia University Irving Medical Center, New York, NY, USA.
³ Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
⁴ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Columbia Center for Translational Immunology, Irving Medical Center, New York, NY, USA.
⁶ Department of Pathology, UNC School of Medicine, Chapel Hill, NC, USA.
⁷ Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
⁹ Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA.
¹² Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA; J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
¹³ Columbia Center for Translational Immunology, Irving Medical Center, New York, NY, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA; Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: ac2248@cumc.columbia.edu.

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.

Keywords: TRPS1; cancer systems biology; gemcitabine; master regulator analysis; regulatory T cells; tumor immunology.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Humans
Lymphocytes, Tumor-Infiltrating / metabolism
Neoplasms* / drug therapy
Neoplasms* / genetics
Neoplasms* / metabolism
Proteins / metabolism
Repressor Proteins / metabolism
T-Lymphocytes, Regulatory* / metabolism

Substances

Proteins
TRPS1 protein, human
Repressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding