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SubmittedOpen Access (License Unspecified), Open
Journal article
Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression
Cell, v 180(6), pp 1098-1114
19 Mar 2020
PMID: 32169218
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor-associated macrophages (TAMs) rather than immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we find that the TME induces tumor cells to produce retinoic acid (RA), which polarizes intratumoral monocyte differentiation toward TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production in tumor cells or pharmacologic inhibition of RA signaling within TME increases stimulatory monocyte-derived cells, enhances T cell-dependent anti-tumor immunity, and synergizes with immune checkpoint blockade. Furthermore, an RA-responsive gene signature in human monocytes correlates with an immunosuppressive TME in multiple human tumors. RA has been considered as an anti-cancer agent, whereas our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.
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Details
- Title
- Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression
- Creators
- Samir Devalaraja - Cancer Research InstituteTsun Ki Jerrick To - Cancer Research InstituteIan W Folkert - Cancer Research InstituteRamakrishnan Natesan - Cancer Research InstituteMd Zahidul Alam - University of PennsylvaniaMinghong Li - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014, USAYuma Tada - University of PennsylvaniaKonstantin Budagyan - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19104, USAMai T Dang - Children's Hospital of PhiladelphiaLi Zhai - University of PennsylvaniaGraham P Lobel - Cancer Research InstituteGabrielle E Ciotti - Cancer Research InstituteT S Karin Eisinger-Mathason - Cancer Research InstituteIrfan A Asangani - Cancer Research InstituteKristy Weber - University of PennsylvaniaM Celeste Simon - Cancer Research InstituteMalay Haldar - Cancer Research Institute
- Publication Details
- Cell, v 180(6), pp 1098-1114
- Number of pages
- 16
- Grant note
- P50 HD105354 / NICHD NIH HHS F30 CA236464 / NCI NIH HHS R37 CA234027 / NCI NIH HHS T32 DK007780 / NIDDK NIH HHS T32 NS007413 / NINDS NIH HHS R01 CA158301 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000520925300009
- Scopus ID
- 2-s2.0-85081901665
- Other Identifier
- 991021860771704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology