Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity

J Exp Med. 2019 Jun 3;216(6):1359-1376. doi: 10.1084/jem.20180660. Epub 2019 Apr 18.


Gastrointestinal stromal tumor (GIST) is driven by an activating mutation in the KIT proto-oncogene. Using a mouse model of GIST and human specimens, we show that intratumoral murine CD103+CD11b- dendritic cells (DCs) and human CD141+ DCs are associated with CD8+ T cell infiltration and differentiation. In mice, the antitumor effect of the Kit inhibitor imatinib is partially mediated by CD103+CD11b- DCs, and effector CD8+ T cells initially proliferate. However, in both mice and humans, chronic imatinib therapy decreases intratumoral DCs and effector CD8+ T cells. The mechanism in our mouse model depends on Kit inhibition, which reduces intratumoral GM-CSF, leading to the accumulation of Batf3-lineage DC progenitors. GM-CSF is produced by γδ T cells via macrophage IL-1β. Stimulants that expand and mature DCs during imatinib treatment improve antitumor immunity. Our findings identify the importance of tumor cell oncogene activity in modulating the Batf3-dependent DC lineage and reveal therapeutic limitations for combined checkpoint blockade and tyrosine kinase inhibition.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinogenesis / drug effects
  • Carcinogenesis / pathology*
  • Cell Differentiation / drug effects
  • Chemotactic Factors / pharmacology
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism*
  • Gastrointestinal Stromal Tumors / immunology*
  • Gastrointestinal Stromal Tumors / pathology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Imatinib Mesylate / pharmacology
  • Immunity* / drug effects
  • Immunologic Memory / drug effects
  • Macrophages / drug effects
  • Macrophages / pathology
  • Mice, Inbred C57BL
  • Monitoring, Immunologic
  • Oncogenes
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Mas
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Repressor Proteins / metabolism*


  • Antigens, CD
  • BATF3 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • Chemotactic Factors
  • MAS1 protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Mas
  • Receptors, Antigen, T-Cell, gamma-delta
  • Repressor Proteins
  • SNFT protein, mouse
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Imatinib Mesylate