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 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.

Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Medina, B. D., Liu, M., Vitiello, G. A., Seifert, A. M., Zeng, S., Bowler, T., Zhang, J. Q., Cavnar, M. J., Loo, J. K., Param, N. J., Maltbaek, J. H., Rossi, F., Balachandran, V., DeMatteo, R. P. Tags: Tumor Immunology Articles Source Type: research