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 6

Agonistic CD40 ligation prevents T cell deletion, priming large numbers of activated T cells, in mice harboring C1498.SIY cells i.v.

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Agonistic CD40 ligation prevents T cell deletion, priming large numbers ...
(A) CFSE dilution of 2C T cells 7 days after transfer into C57BL/6 mice challenged with i.v. C1498.SIY cells and treated with anti-CD40 or isotype control Ab (IC). (B) Splenocytes from mice in A were restimulated with media or SIY peptide, and IFN-γ and TNF-α production by 2C T cells was assessed. Numbers represent percent cytokine-producing 2C T cells. (C) C57BL/6 mice received i.v. or s.c. C1498.SIY cells and were treated with anti-CD40 or isotype control Ab. On day 6, percent SIY-reactive splenic CD8+ T cells was analyzed. A negative control OVA tetramer was also used. *P < 0.05 versus all other groups. (D) IFN-γ ELISPOT analysis of splenocytes from mice in C. *P < 0.05 versus control Ab. (E) C57BL/6 mice received C1498.SIY cells i.v. on day –6 and were treated with anti-CD40 or isotype control Ab on days –6 and –3. On day 0, these mice were challenged with C1498.SIY cells s.c. Control mice received C1498.SIY cells i.v. or s.c. on day 0 only. IFN-γ ELISPOT analysis was performed on day 6. (F) C57BL/6 mice received C1498.SIY cells i.v. On days 0, 2, and 4, anti-CD40 or isotype control Ab was administered, and survival was assessed. *P = 0.002 versus control Ab. (G) C57BL/6 mice received i.v. C1498.SIY cells on day 0. On days 8, 10, 12, 17, 22, and 27, anti-CD40 or isotype control Ab was administered, and survival was assessed. *P = 0.05 versus control Ab. (H) C57BL/6 mice received FBL cells i.v. on day 0. On days 5, 7, 9, 13, and 18, anti-CD40 or isotype control Ab was administered, and survival was assessed. *P < 0.05 versus control Ab. Data are representative of 2 independent experiments with 3 (A–E) or 5 (F–H) mice/group.