PD-1H/VISTA mediates immune evasion in acute myeloid leukemia
Tae Kon Kim, … , Steven D. Gore, Lieping Chen
Tae Kon Kim, … , Steven D. Gore, Lieping Chen
Published December 7, 2023
Citation Information: J Clin Invest. 2024;134(3):e164325. https://doi.org/10.1172/JCI164325.
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Research Article Immunology Oncology

PD-1H/VISTA mediates immune evasion in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti–programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell–mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD-1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD-1H as a potential therapeutic target for treating human AML.

Authors

Tae Kon Kim, Xue Han, Qianni Hu, Esten N. Vandsemb, Carly M. Fielder, Junshik Hong, Kwang Woon Kim, Emily F. Mason, R. Skipper Plowman, Jun Wang, Qi Wang, Jian-Ping Zhang, Ti Badri, Miguel F. Sanmamed, Linghua Zheng, Tianxiang Zhang, Jude Alawa, Sang Won Lee, Amer M. Zeidan, Stephanie Halene, Manoj M. Pillai, Namrata S. Chandhok, Jun Lu, Mina L. Xu, Steven D. Gore, Lieping Chen

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Figure 3

Host-derived PD-1H induces immune evasion in AML.

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Host-derived PD-1H induces immune evasion in AML. (A) Syngeneic mouse le...
(A) Syngeneic mouse leukemia model using tail-vein injection with myeloid leukemia cells (C1498). Mouse leukemia cells (C1498FF-mock) were transplanted into B6 PD-1H WT or PD-1H–KO mice or lineage-specific PD-1H–KO mice. In vivo proliferation was assessed by bioluminescence. (B) In vivo antileukemia effect of genetic deletion of PD-1H in host mice. Radiance indicates the mean value per group, and error bars represent SEM. P value determined by Student’s t test at each time point. n = 5 per group; *P < 0.05. These experiments were repeated 3 times. Repeated measures were determined by ANOVA with 2 factors (P > 0.05, no difference among experiments). (C) In vivo antileukemia effect of myeloid lineage–specific deletion of PD-1H in host mice. Bioluminescence was compared in LysM-Cre+PD-1H-floxed mice with control–PD-1H-floxed mice. Radiance indicates the mean value per group, and error bars represent SEM. P value determined by Student’s t test at each time point. *P < 0.05. n = 9 per group. Representative data from 2 independent experiments were combined. Repeated measures were determined by ANOVA (P > 0.05, no difference among experiments). (D) In vivo antileukemia effect of T cell lineage–specific deletion of PD-1H in host mice. Bioluminescence was compared in Lck-Cre+PD-1H-floxed mice versus control–PD-1H-floxed mice. Radiance indicates the mean value per group, and error bars represent SEM. P value determined by Student’s t test at each time point. Error bars represent SEM. n = 6 per group. Repeated measures were determined by ANOVA (P > 0.05, no difference among experiments).