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Author Notes:

David H. Munn, MD, Professor of Pediatric Oncology, Pediatric Immunotherapy Program, Georgia Cancer Center, Room CN-4141, Medical College of Georgia, Augusta University, 1120 Fifteenth St. , Augusta, GA 30912, Tel. 706.721.7141 | Fax 706.721.4804. Email: dmunn@augusta.edu

Madhav D. Sharma – designed and conducted experiments Rafal Pacholczyk – analyzed scRNA-seq data for mouse cells; performed UMAP analysis of published human scRNA-seq datasets; analyzed kynurenine assays Huidong Shi – performed and analyzed ATAC-seq assays and mouse bulk RNA-seq Zuzana Berrong – performed kynurenine assays Yousef Zakharia – provided clinical samples and reviewed and discussed the manuscript Austin Greco – provided clinical samples Chang-Sheng S. Chang – performed analysis of scRNA-seq for mouse cells Sudharshan Eathiraj – provided reagents and reviewed and discussed the manuscript Eugene Kennedy – provided reagents and reviewed and discussed the manuscript Thomas Cash – provided clinical samples and reviewed and discussed the manuscript Roni Bollag – provided clinical samples and reviewed and discussed the manuscript Ravindra Kolhe – provided clinical samples and reviewed and discussed the manuscript Ramses Sadek – biostatistician Tracy McGaha – helped conceptualize experiments and reviewed and discussed the manuscript Paulo Rodriguez – helped conceptualize experiments and reviewed and discussed the manuscript Bruce R. Blazar – helped conceptualize experiments and reviewed and discussed the manuscript Theodore S. Johnson – helped conceptualize experiments and reviewed and discussed the manuscript David H. Munn – designed the experiments, analyzed data, made the figures, wrote the manuscript, lead contact and corresponding author

The authors thank Anita Sharma, Joyce Wilson and Gabriela Pacholczyk for expert technical assistance; Jeanene Pihkala and the Cancer Center Flow Cytometry Core for cell-sorting; Eiko Kitamura and the Cancer Center Integrated Genomics Core for single-cell sequencing; and Dr. S. Chen, Rutgers University, for the gift of Tg(Grm1)Epv mice. Supported by NIH R01CA103320 and R01CA211229 to D.H.M.; R50CA232983 to M.D.S.; R01HL56067 and R01HL11879 to B.R.B.; and support from the Press-On Foundation and the Beloco Foundation to D.H.M. and T.S.J.

Y.Z. has received clinical trial support from NewLink Genetics (now Lumos Pharma). S. E. was an employee of ArQule, Inc. (now a wholly-owned subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA), which holds the rights to ArQ531. E.K. was an employee of NewLink Genetics (now Lumos Pharma). T.L.M. receives consulting income from FLX Therapeutics. B.R.B. holds intellectual property interests in the therapeutic use of IDO inhibitors; receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; receives research funding from BlueRock Therapeutics, Rheos Medicines, and Equilibre Biopharmaceuticals Corp. T.S.J. has received clinical trial funding from NewLink Genetics (now Lumos Pharma). D.H.M. (corresponding author) holds patents and intellectual property interests in the therapeutic use of IDO inhibitors; and has received consulting income and research support from NewLink Genetics (now Lumos Pharma). The other authors declare no competing interests.

Subjects:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • ANTIGEN-PRESENTING CELLS
  • BRUTONS TYROSINE KINASE
  • INDOLEAMINE 2,3-DIOXYGENASE
  • CHEMOTHERAPY
  • DEFICIENCY
  • MATURATION
  • REVEALS
  • SUBSET

Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity

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Journal Title:

IMMUNITY

Volume:

Volume 54, Number 10

Publisher:

, Pages 2354-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Monocytic-lineage inflammatory Ly6c+CD103+ dendritic cells (DCs) promote antitumor immunity, but these DCs are infrequent in tumors, even upon chemotherapy. Here, we examined how targeting pathways that inhibit the differentiation of inflammatory myeloid cells affect antitumor immunity. Pharmacologic inhibition of Bruton's tyrosine kinase (BTK) and the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) or deletion of Btk or Ido1 allowed robust differentiation of inflammatory Ly6c+CD103+ DCs during chemotherapy, promoting antitumor T cell responses and inhibiting tumor growth. Immature Ly6c+c-kit+ precursor cells had epigenetic profiles similar to conventional DC precursors; deletion of Btk or Ido1 promoted differentiation of these cells. Mechanistically, a BTK-IDO axis inhibited a tryptophan-sensitive differentiation pathway driven by GATOR2 and mTORC1, and disruption of the GATOR2 in monocyte-lineage precursors prevented differentiation into inflammatory DCs in vivo. IDO-expressing DCs and monocytic cells were present across a range of human tumors. Thus, a BTK-IDO axis represses differentiation of inflammatory DCs during chemotherapy, with implications for targeted therapies.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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