PD-1H/VISTA mediates immune evasion in acute myeloid leukemia
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
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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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 6

Mouse PD-1H blockade confers a synergistic antileukemic effect with mouse PD-1 blockade.

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Mouse PD-1H blockade confers a synergistic antileukemic effect with mous...
(A) Syngeneic mouse leukemia model using tail-vein injection with mouse myeloid leukemia cells expressing PD-1H (C1498FF–PD-1H) transplanted into B6 mice, which were then treated with anti–PD-1 and/or anti–PD-1H mAbs. Syngeneic mouse leukemia model using tail-vein injection with mouse myeloid leukemia cells not expressing PD-1H (C1498FF-mock) transplanted into WT B6 mice or PD-1H–KO mice, which were then assessed for in vivo antileukemia effect of genetic deletion of PD-1H in host mice with or without anti–PD-1 mAbs. (B) Synergistic antileukemia effect of anti–PD-1 mAb with anti–PD-1H mAb. In vivo proliferation was assessed by bioluminescence (left) and survival by a Kaplan-Meier plot (right). Radiance indicates the mean value per group, and error bars represent SEM. Data from 2 experiments were combined (n = 10). (C) Synergistic antileukemia effect of genetic deletion of PD-1H in host mice (PD-1H KO) with anti–PD-1 mAb. In vivo proliferation was assessed by bioluminescence (left) and survival by a Kaplan-Meier plot (right). Radiance indicates the mean value per group, and error bars represent SEM. Data from 2 experiments were combined (n = 10). (B and C) P value determined by simple linear regression method for statistical analysis of radiance and log-rank test for survival. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. These experiments were repeated 2 times. Repeated measures were determined by ANOVA with 2 factors (P > 0.05, no difference among experiments).