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

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.