| First Author | Medina BD | Year | 2019 |
| Journal | J Exp Med | Volume | 216 |
| Issue | 6 | Pages | 1359-1376 |
| PubMed ID | 31000683 | Mgi Jnum | J:277919 |
| Mgi Id | MGI:6315062 | Doi | 10.1084/jem.20180660 |
| Citation | Medina BD, et al. (2019) Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity. J Exp Med 216(6):1359-1376 |
| abstractText | 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 gammadelta T cells via macrophage IL-1beta. 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. |
