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

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.
Article Title: Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity
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. © 2019 Medina et al.
Journal Title: Journal of Experimental Medicine
Volume: 216
Issue: 6
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2019-06-03
Start Page: 1359
End Page: 1376
Language: English
DOI: 10.1084/jem.20180660
PUBMED: 31000683
PROVIDER: scopus
PMCID: PMC6547861
Notes: Source: Scopus
Citation Impact
MSK Authors
  1. Ronald P DeMatteo
    636 DeMatteo
  2. Michael Joseph Cavnar
    30 Cavnar
  3. Ferdinando Rossi
    23 Rossi
  4. Shan Zeng
    26 Zeng
  5. Adrian Marcel Seifert
    16 Seifert
  6. Jennifer Qi Zhang
    27 Zhang
  7. Benjamin Medina
    15 Medina
  8. Jennifer Loo
    13 Loo
  9. Timothy Geoffrey Bowler
    9 Bowler
  10. Nesteene Joy Param
    6 Param
  11. Mengyuan Liu
    5 Liu