TY - JOUR
T1 - Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators
AU - Obradovic, Aleksandar
AU - Ager, Casey
AU - Turunen, Mikko
AU - Nirschl, Thomas
AU - Khosravi-Maharlooei, Mohsen
AU - Iuga, Alina
AU - Jackson, Christopher M.
AU - Yegnasubramanian, Srinivasan
AU - Tomassoni, Lorenzo
AU - Fernandez, Ester Calvo
AU - McCann, Patrick
AU - Rogava, Meri
AU - DeMarzo, Angelo M.
AU - Kochel, Christina M.
AU - Allaf, Mohamad
AU - Bivalacqua, Trinity
AU - Lim, Michael
AU - Realubit, Ronald
AU - Karan, Charles
AU - Drake, Charles G.
AU - Califano, Andrea
N1 - Funding Information:
This research was supported by National Institutes of Health (NIH) grants R01 CA127153 , 1P50CA58236-15 , and P30CA006973 , the Prostate Cancer Foundation Challenge Grant, and CUMC institutional funds to C.G.D.; by NIH grants R35CA197745 , U01DA217858 , S10 OD012351 , and S10 OD021764 to A.C.; by NIH grant F30CA260765-01 to A.O.; and by NIH grants UL1TR001873 and TL1TR001875 to C.A. This study was also supported by the Sigrid Jusélius Foundation (M.T.). We thank the Sidney Kimmel Comprehensive Cancer Center Experimental and Computational Genomics Core at Johns Hopkins, supported by NIH / NCI grant P30CA006973 , for support in performing the bulk-RNA sequencing on sorted cells from human cancer subjects. We also thank Drs. A. Jolma and J. Taipale for kindly providing some of the full-length cDNA of the TI-TREG MRs. This study was also supported by the NIH / NCI SPORE in Prostate Cancer ( P50CA58236 ) and the US Department of Defense Prostate Cancer Research Program ( PCRP ) Prostate Cancer Biospecimen Network Site ( W81XWH-18-2-0015 ).
Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/5/8
Y1 - 2023/5/8
N2 - 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.
AB - 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.
KW - TRPS1
KW - cancer systems biology
KW - gemcitabine
KW - master regulator analysis
KW - regulatory T cells
KW - tumor immunology
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U2 - 10.1016/j.ccell.2023.04.003
DO - 10.1016/j.ccell.2023.04.003
M3 - Article
C2 - 37116491
AN - SCOPUS:85154038066
SN - 1535-6108
VL - 41
SP - 933-949.e11
JO - Cancer cell
JF - Cancer cell
IS - 5
ER -