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

Benjamin D. Medina, Mengyuan Liu, Gerardo A. Vitiello, Adrian M. Seifert, Shan Zeng, Timothy Bowler, Jennifer Q. Zhang, Michael J. Cavnar, Jennifer K. Loo, Nesteene J. Param, Joanna H. Maltbaek, Ferdinand Rossi, Vinod Balachandran, Ronald P. DeMatteo

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Pages (from-to)1359-1376
Number of pages18
JournalJournal of Experimental Medicine
Volume216
Issue number6
DOIs
StatePublished - Jun 1 2019

Bibliographical note

Publisher Copyright:
© 2019 Medina et al.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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