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

doi:10.1084/jem.20180660

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

Surgery

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	1359-1376
Number of pages	18
Journal	Journal of Experimental Medicine
Volume	216
Issue number	6
DOIs	https://doi.org/10.1084/jem.20180660
State	Published - Jun 1 2019

Bibliographical note

Publisher Copyright:
© 2019 Medina et al.

Funding

The investigators were supported by NIH grants R01 CA102613 and T32 CA09501, Betsy Levine-Brown and Marc Brown, David and Monica Gorin, The David Foundation, the GIST Cancer Research Fund (R.P. DeMatteo), NIH grant F32 CA186534 (J.Q. Zhang), and NIH grant L30 TR002111 (G.A. Vitiello). The Flow Cytometry and Molecular Cytology Core Facilities were supported by National Cancer Institute Cancer Center Support Grant P30 CA008748. The authors declare no competing financial interests.

Funders	Funder number
David C. Copley Foundation
National Institutes of Health (NIH)	R01 CA102613
National Childhood Cancer Registry – National Cancer Institute	P30 CA008748, T32CA009501
Gwangju Institute of Science and Technology	L30 TR002111, F32 CA186534

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1084/jem.20180660

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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. (2019). Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity. Journal of Experimental Medicine, 216(6), 1359-1376. https://doi.org/10.1084/jem.20180660

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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.",

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

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Medina, BD, Liu, M, Vitiello, GA, Seifert, AM, Zeng, S, Bowler, T, Zhang, JQ, Cavnar, MJ, Loo, JK, Param, NJ, Maltbaek, JH, Rossi, F, Balachandran, V & DeMatteo, RP 2019, 'Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity', Journal of Experimental Medicine, vol. 216, no. 6, pp. 1359-1376. https://doi.org/10.1084/jem.20180660

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AU - Medina, Benjamin D.

AU - Liu, Mengyuan

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AU - Zeng, Shan

AU - Bowler, Timothy

AU - Zhang, Jennifer Q.

AU - Cavnar, Michael J.

AU - Loo, Jennifer K.

AU - Param, Nesteene J.

AU - Maltbaek, Joanna H.

AU - Rossi, Ferdinand

AU - Balachandran, Vinod

AU - DeMatteo, Ronald P.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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