Abstract
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.
© 2019 Medina et al.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / metabolism
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Basic-Leucine Zipper Transcription Factors / metabolism*
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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Carcinogenesis / drug effects
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Carcinogenesis / pathology*
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Cell Differentiation / drug effects
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Chemotactic Factors / pharmacology
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Dendritic Cells / drug effects
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Dendritic Cells / metabolism*
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Gastrointestinal Stromal Tumors / immunology*
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Gastrointestinal Stromal Tumors / pathology*
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Imatinib Mesylate / pharmacology
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Immunity* / drug effects
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Immunologic Memory / drug effects
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Macrophages / drug effects
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Macrophages / pathology
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Mice, Inbred C57BL
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Monitoring, Immunologic
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Oncogenes
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Mas
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Receptors, Antigen, T-Cell, gamma-delta / metabolism
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Repressor Proteins / metabolism*
Substances
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Antigens, CD
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BATF3 protein, human
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Basic-Leucine Zipper Transcription Factors
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Chemotactic Factors
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MAS1 protein, human
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Protein Kinase Inhibitors
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Proto-Oncogene Mas
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Receptors, Antigen, T-Cell, gamma-delta
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Repressor Proteins
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SNFT protein, mouse
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Granulocyte-Macrophage Colony-Stimulating Factor
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Imatinib Mesylate