Sharma et al. showed that blockade of BTK and tryptophan-degrading IDO synergized with chemotherapy to differentiate epigenetically poised BTK+IDO+Ly6c+c-kit+ monocyte lineage precursors present in murine tumors into inflammatory committed Ly6c+CD103+ DCs. Treated host mice rapidly regressed tumors, expressed less PD-1 and more activation markers on anti- tumor CD8+ T cells, and had tumor Tregs with a disrupted phenotype. DC differentiation induced by chemotherapy + BTK/IDO blockade required signaling by the amino acid-sensitive GATOR2/ mTORC1 complex. BTK+ and IDO+ DCs were identified in a variety of human tumor types.
Contributed by Paula Hochman
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.
Author Info: (1) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta
Author Info: (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) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. (4) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. (5) Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA. (6) Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA. (7) 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. (8) ArQule, Burlington, MA 01803, USA. (9) Lumos Pharma, Ames, IA 50010, USA. (10) Department of Pediatrics, Emory University, Atlanta, GA 30322, USA. (11) 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. (12) Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. (13) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. (14) Department of Immunology, University of Toronto, Toronto, ON M5G 2M9, Canada. (15) Immunology Department, Moffitt Cancer Center, Tampa, FL 33612, USA. (16) Immunology Department, Moffitt Cancer Center, Tampa, FL 33612, USA. (17) Department of Pediatrics and Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA. (18) 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. (19) 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: dmunn@augusta.edu.
