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

Madhav D. Sharma, Rafal Pacholczyk, Huidong Shi, Zuzana J. Berrong, Yousef Zakharia, Austin Greco, Chang Sheng S. Chang, Sudharshan Eathiraj, Eugene Kennedy, Thomas Cash, Roni J. Bollag, Ravindra Kolhe, Ramses Sadek, Tracy L. McGaha, Paulo Rodriguez, Jessica Mandula, Bruce R. Blazar, Theodore S. Johnson, David H. Munn

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2354-2371.e8
JournalImmunity
Volume54
Issue number10
DOIs
StatePublished - Oct 12 2021

Bibliographical note

Funding Information:
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. This work was 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.). M.D.S. designed and conducted experiments. R.P. analyzed scRNA-seq data for mouse cells, performed the UMAP analysis of published human scRNA-seq datasets, and analyzed the kynurenine assays. H.S. performed and analyzed the ATAC-seq assays and the mouse bulk RNA-seq. Z.J.B. performed the kynurenine assays. Y.Z. provided the clinical samples and reviewed and discussed the manuscript. A.G. provided the clinical samples. C.-S.S.C. performed the analysis of scRNA-seq for mouse cells. S.E. provided reagents and reviewed and discussed the manuscript. E.K. provided reagents and reviewed and discussed the manuscript. T.C. provided the clinical samples and reviewed and discussed the manuscript. R.J.B. provided clinical samples and reviewed and discussed the manuscript. R.K. provided clinical samples and reviewed and discussed the manuscript. R.S. was the biostatistician for the study. T.L.M. helped conceptualize the experiments and reviewed and discussed the manuscript. P.R. and J.M. helped conceptualize the experiments and reviewed and discussed the manuscript. B.R.B. helped conceptualize the experiments and reviewed and discussed the manuscript. T.S.J. helped conceptualize the experiments and reviewed and discussed the manuscript. D.H.M. designed the experiments, analyzed the data, created the figures, and wrote the manuscript. Y.Z. has received clinical trial support from NewLink Genetics (now Lumos Pharma), which holds the rights to indoximod. S.E. was an employee of ArQule (now a wholly owned subsidiary of Merck & Co. 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; and receives research funding from BlueRock Therapeutics, Rheos Medicines, and Equilibre Biopharmaceuticals. T.S.J. has received clinical trial funding from NewLink Genetics (now Lumos Pharma). D.H.M. 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.

Funding Information:
Y.Z. has received clinical trial support from NewLink Genetics (now Lumos Pharma), which holds the rights to indoximod. S.E. was an employee of ArQule (now a wholly owned subsidiary of Merck & Co., 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; and receives research funding from BlueRock Therapeutics, Rheos Medicines, and Equilibre Biopharmaceuticals. T.S.J. has received clinical trial funding from NewLink Genetics (now Lumos Pharma). D.H.M. 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.

Funding Information:
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. This work was 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.).

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • BTK
  • Bruton's tyrosine kinase
  • IDO
  • antigen-presenting cells
  • chemotherapy
  • dendritic cells
  • immunotherapy
  • indoleamine 2,3-dioxygenase
  • tumors

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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