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

Autor:	Medina BD; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Liu M; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.; Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA., Vitiello GA; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Seifert AM; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Zeng S; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Bowler T; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Zhang JQ; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Cavnar MJ; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Loo JK; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Param NJ; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Maltbaek JH; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Rossi F; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., Balachandran V; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY., DeMatteo RP; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY ronald.dematteo@uphs.upenn.edu.; Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2019 Jun 03; Vol. 216 (6), pp. 1359-1376. Date of Electronic Publication: 2019 Apr 18.
DOI:	10.1084/jem.20180660
Abstrakt:	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.)
Databáze:	MEDLINE
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