Chimeric antigen receptor T cells shape myeloid cell function within the tumor microenvironment through IFN-γ and GM-CSF.

The Journal of Immunology : Official Journal of the American Association of Immunologists
Paul SpearCharles L Sentman

Abstract

The infiltration of suppressive myeloid cells into the tumor microenvironment restrains anti-tumor immunity. However, cytokines may alter the function of myeloid lineage cells to support tumor rejection, regulating the balance between pro- and anti-tumor immunity. In this study, it is shown that effector cytokines secreted by adoptively transferred T cells expressing a chimeric Ag receptor (CAR) shape the function of myeloid cells to promote endogenous immunity and tumor destruction. Mice bearing the ovarian ID8 tumor were treated with T cells transduced with a chimeric NKG2D receptor. GM-CSF secreted by the adoptively transferred T cells recruited peripheral F4/80(lo)Ly-6C(+) myeloid cells to the tumor microenvironment in a CCR2-dependent fashion. T cell IFN-γ and GM-CSF activated local, tumor-associated macrophages, decreased expression of regulatory factors, increased IL-12p40 production, and augmented Ag processing and presentation by host macrophages to Ag-specific T cells. In addition, T cell-derived IFN-γ, but not GM-CSF, induced the production of NO by F4/80(hi) macrophages and enhanced their lysis of tumor cells. The ability of CAR T cell therapy to eliminate tumor was moderately impaired when inducible NO synthase was...Continue Reading

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Citations

Feb 8, 2014·Journal of Hematology & Oncology·Zhao SunRobert Chunhua Zhao
May 1, 2013·Immunology and Cell Biology·Paul SpearCharles L Sentman
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Nov 17, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Marie-Louise SentmanCharles L Sentman
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