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Published on: January 7, 2019
Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity
Benjamin D Medina1, Mengyuan Liu1,2, Gerardo A Vitiello1
1Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.
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.
Insights
Gastrointestinal stromal tumor (GIST) treatment with imatinib reduces beneficial dendritic cells (DCs) and CD8+ T cells. Strategies to boost DCs during therapy may enhance anti-GIST immunity.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Gastrointestinal stromal tumors (GIST) are driven by KIT proto-oncogene mutations.
- Dendritic cells (DCs) and CD8+ T cells play roles in anti-tumor immunity.
- Imatinib is a tyrosine kinase inhibitor used to treat GIST.
Purpose of the Study:
- To investigate the role of specific dendritic cell subsets in GIST immunity.
- To elucidate the impact of imatinib therapy on these immune cells.
- To identify strategies for improving anti-tumor immunity during GIST treatment.
Main Methods:
- Utilized a mouse model of GIST and human tumor specimens.
- Analyzed intratumoral dendritic cell populations (CD103+CD11b- in mice, CD141+ in humans).
- Assessed CD8+ T cell infiltration and differentiation.
- Investigated the role of GM-CSF and IL-1β in the observed immune changes.
- Evaluated the effect of enhancing DC maturation during imatinib treatment.
Main Results:
- Intratumoral CD103+CD11b- DCs (mice) and CD141+ DCs (humans) correlate with CD8+ T cell infiltration.
- Imatinib's anti-tumor effect involves CD103+CD11b- DCs and initial CD8+ T cell proliferation.
- Chronic imatinib therapy reduces intratumoral DCs and effector CD8+ T cells.
- Kit inhibition decreases GM-CSF, impacting Batf3-lineage DC progenitors.
- GM-CSF production involves γδ T cells and macrophage IL-1β.
- Stimulating DC expansion and maturation enhances anti-tumor immunity during imatinib treatment.
Conclusions:
- Tumor oncogene activity influences Batf3-dependent DC lineage.
- Chronic imatinib therapy can impair crucial anti-tumor immune cells.
- Therapeutic strategies combining checkpoint blockade with tyrosine kinase inhibitors may face limitations.
- Enhancing DC function during imatinib treatment holds promise for improving GIST immunotherapy.
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