PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.

Autor:	Basavaraja R; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Zhang H; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Holczbauer Á; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Lu Z; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Radaelli E; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Assenmacher CA; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., George SS; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Nallamala VC; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Beiting DP; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Meyer-Ficca ML; Department of Veterinary Clinical and Life Sciences, College of Veterinary Medicine, Utah State University, Logan, UT 84332, USA., Meyer RG; Department of Veterinary Clinical and Life Sciences, College of Veterinary Medicine, Utah State University, Logan, UT 84332, USA., Guo W; Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA., Fan Y; Departments of Radiation Oncology and of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Modzelewski AJ; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Spiegelman VS; Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA., Cohen MS; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA., Fuchs SY; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: syfuchs@upenn.edu.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Jul 16; Vol. 5 (7), pp. 101649.
DOI:	10.1016/j.xcrm.2024.101649
Abstrakt:	Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies. Competing Interests: Declaration of interests M.S.C. is an inventor on an OHSU patent related to the general use of the ITK7 compound. M.S.C., R.B., and S.Y.F. are co-inventors on a pending patent from OHSU/University of Pennsylvania related to ITK7 use. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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