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, 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
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.
Keywords: BTK; Bruton's tyrosine kinase; IDO; antigen-presenting cells; chemotherapy; dendritic cells; immunotherapy; indoleamine 2,3-dioxygenase; tumors.
Conflict of interest statement
Declaration of interests 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.
Copyright © 2021 Elsevier Inc. All rights reserved.
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Source: PubMed