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

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.

• Authors: 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
• Journal: Immunity (Immunity) Vol. 54 Issue 10 Pg. 2354-2371.e8 (10 12 2021) ISSN: 1097-4180 [Electronic] United States
• PMID: 34614413 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Agammaglobulinaemia Tyrosine Kinase
• TOR Serine-Threonine Kinases

Topics

• Agammaglobulinaemia Tyrosine Kinase (immunology, metabolism)
• Animals
• Cell Differentiation (immunology)
• Dendritic Cells (cytology, immunology, metabolism)
• Female
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (immunology, metabolism)
• Male
• Mice
• Monocytes (cytology, immunology, metabolism)
• Neoplasms (immunology)
• Signal Transduction (immunology)
• T-Lymphocytes (immunology, metabolism)
• TOR Serine-Threonine Kinases (immunology, metabolism)