title: CD40 ligation reverses T cell tolerance in acute myeloid leukemia.
abstract: Spontaneous antigen-specific T cell responses can be generated in hosts harboring a variety of solid malignancies, but are subverted by immune evasion mechanisms active within the tumor microenvironment. In contrast to solid tumors, the mechanisms that regulate T cell activation versus tolerance to hematological malignancies have been underexplored. A murine acute myeloid leukemia (AML) model was used to investigate antigen-specific T cell responses against AML cells inoculated i.v. versus s.c. Robust antigen-specific T cell responses were generated against AML cells after s.c., but not i.v., inoculation. In fact, i.v. AML cell inoculation prevented functional T cell activation in response to subsequent s.c. AML cell challenge. T cell dysfunction was antigen specific and did not depend on Tregs or myeloid-derived suppressor cells (MDSCs). Antigen-specific TCR-Tg CD8+ T cells proliferated, but failed to accumulate, and expressed low levels of effector cytokines in hosts after i.v. AML induction, consistent with abortive T cell activation and peripheral tolerance. Administration of agonistic anti-CD40 Ab to activate host APCs enhanced accumulation of functional T cells and prolonged survival. Our results suggest that antigen-specific T cell tolerance is a potent immune evasion mechanism in hosts with AML that can be reversed in vivo after CD40 engagement.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiufen
authors.initials: X
authors.lastname: Chen
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Kline
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Teague
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.forename: Justin
authors.initials: J
authors.lastname: Kline
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000166:cytology*; D013997:Time Factors
chemical_list: D019013:CD40 Antigens; D007371:Interferon-gamma