CD40 ligation reverses T cell tolerance in acute myeloid leukemia
Long Zhang, … , Thomas F. Gajewski, Justin Kline
Long Zhang, … , Thomas F. Gajewski, Justin Kline
Published April 24, 2013
Citation Information: J Clin Invest. 2013;123(5):1999-2010. https://doi.org/10.1172/JCI63980.
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Research Article

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

Long Zhang, Xiufen Chen, Xiao Liu, Douglas E. Kline, Ryan M. Teague, Thomas F. Gajewski, Justin Kline

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Figure 3

T cell dysfunction in mice after i.v. C1498.SIY cell inoculation is antigen specific, and is not regulated by Tregs or MDSCs.

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T cell dysfunction in mice after i.v. C1498.SIY cell inoculation is anti...
(A) C57BL/6 mice received 106 C1498.SIY or B16.OVA cells s.c. only. Additional cohorts of mice received 106 C1498.SIY cells i.v. on day –6, followed by either C1498.SIY or B16.OVA cells s.c. on day 0. On day 6, spleen cells were restimulated with SIY or OVA peptide in an IFN-γ ELISPOT assay. *P < 0.05. (B) FoxP3-DTR mice received C1498.SIY cells s.c. or i.v./s.c. and were treated with diphtheria toxin (DT; 1 μg in 0.1 ml per mouse) or PBS as follows: s.c. C1498.SIY cell–challenged mice, days –2, –1, 0, 2, and 5; i.v./s.c. C1498.SIY cell–challenged mice, days –8, –7, –4, –1, 2, and 5. On day 6, an IFN-γ ELISPOT assay was performed. (C) C57BL/6 mice received s.c. or i.v./s.c. C1498.SIY cells and received either the anti–Ly-6G Ab 1A8 or isotype control Ab (300 μg i.p. on days 0 and 3 for s.c. challenge, and on days –6, –3, 0, and 3 for i.v./s.c. challenge). On day 6, spleen cells were restimulated with media or SIY peptide in an IFN-γ ELISPOT assay. (A–C) Data are representative of 2 experiments with 3 mice/group.