title: Chimeric antigen receptor T cells shape myeloid cell function within the tumor microenvironment through IFN-γ and GM-CSF.
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 inhibited and greatly impaired in the absence of peritoneal macrophages after depletion with clodronate encapsulated liposomes. This study demonstrates that the activation of host macrophages by CAR T cell-derived cytokines transformed the tumor microenvironment from immunosuppressive to immunostimulatory and contributed to inhibition of ovarian tumor growth.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Spear
authors.forename: Amorette
authors.initials: A
authors.lastname: Barber
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Rynda-Apple
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sentman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002678:Chimera; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor