Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity PMID: 34614413

ADC Targets in Oncology

2026-04-10

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

Immunity. 2021 Oct 12;54(10):2354-2371.e8. doi: 10.1016/j.immuni.2021.09.005.

Madhav D Sharma ¹ , Rafal Pacholczyk ² , Huidong Shi ² , Zuzana J Berrong ² , Yousef Zakharia ³ , Austin Greco ³ , Chang-Sheng S Chang ⁴ , Sudharshan Eathiraj ⁵ , Eugene Kennedy ⁶ , Thomas Cash ⁷ , Roni J Bollag ⁸ , Ravindra Kolhe ⁹ , Ramses Sadek ² , Tracy L McGaha ¹⁰ , Paulo Rodriguez ¹¹ , Jessica Mandula ¹¹ , Bruce R Blazar ¹² , Theodore S Johnson ¹ , David H Munn ¹³

Affiliations

1. Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
2. Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
3. Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
4. Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Georgia Cancer Center, Bioinformatics Shared Resource, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
5. ArQule, Burlington, MA 01803, USA.
6. Lumos Pharma, Ames, IA 50010, USA.
7. Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
8. Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
9. Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
10. Department of Immunology, University of Toronto, Toronto, ON M5G 2M9, Canada.
11. Immunology Department, Moffitt Cancer Center, Tampa, FL 33612, USA.
12. Department of Pediatrics and Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
13. Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Electronic address: [email protected].

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.