CD40 ligation reverses T cell tolerance in acute myeloid leukemia
Long Zhang, Xiufen Chen, Xiao Liu, Douglas E. Kline, Ryan M. Teague, Thomas F. Gajewski, Justin Kline
Long Zhang, Xiufen Chen, Xiao Liu, Douglas E. Kline, Ryan M. Teague, Thomas F. Gajewski, Justin Kline
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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 2

Inoculation of C1498.SIY cells i.v. generates a T cell–dysfunctional state.

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Inoculation of C1498.SIY cells i.v. generates a T cell–dysfunctional sta...
(A and B) C1498.SIY cells were inoculated into C57BL/6 mice i.v., s.c., or i.v./s.c. Spleen (A) and LN (B) cells were restimulated 6 days later with media or SIY peptide, and IFN-γ ELISPOT was performed. *P < 0.05. Data are representative of 3 independent experiments with 3 mice/group. (C) 6 days after inoculation of control C1498 cells i.v., s.c., or i.v./s.c., LN cells were restimulated with media or irradiated C1498 cells in an IFN-γ ELISPOT assay. *P < 0.05. (D) Indicated numbers of i.v. C1498.SIY cells were introduced on day –6, followed by 106 s.c. C1498.SIY cells on day 0. On day 6, IFN-γ ELISPOT was performed. *P < 0.05 versus all other groups. (E) Mice received C1498.SIY cells as in A. A fourth group received s.c. C1498.SIY cells in one flank on day –6, and the opposite flank on day 0 (s.c./s.c.). IFN-γ ELISPOT was performed on day 6. *P < 0.05. (F) Live or irradiated C1498.SIY cells were inoculated i.v., s.c., or i.v./s.c., and IFN-γ ELISPOT was performed. *P < 0.05. (C–F) Data are representative of 2 experiments with 3 mice/group.