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 2

AML surface PD-1H inhibits T cell infiltration, leading to immune evasion.

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AML surface PD-1H inhibits T cell infiltration, leading to immune evasio...
(A) Syngeneic mouse leukemia model using tail-vein injection with myeloid leukemia cells (C1498). Mouse leukemia cells expressing PD-1H (C1498FF–PD-1H) or cells not expressing PD-1H (C1498FF-mock) were transplanted into B6 mice and assessed for in vivo leukemia proliferation using bioluminescence. (B) In vivo proliferation of C1498FF-mock versus C1498FF–PD-1H cells in B6 WT mice (n = 7). 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; ***P < 0.001. 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 proliferation of C1498FF-mock versus C1498FF–PD-1H cells in NSG mice (n = 3) (representative images on day 21 on the right side). Radiance indicates the mean value per group, and error bars represent SEM. P value determined by Student’s t test at each time point. Repeated measures were determined by ANOVA with 2 factors (P > 0.05, no difference among experiments). (D) In vitro growth of C1498FF–PD-1H tumors compared with C1498FF-mock tumors. Statistical analysis was done using Student’s t test. (E) Syngeneic mouse model using s.c. injection with C1498 cells. C1498FF–PD-1H cells or C1498FF-mock cells were s.c. injected into the flanks of B6 mice and the tumor volume was assessed. Mean tumor volume ± SEM. P value determined by Student’s t test at each time point. n = 5 per group; P = 0.07. Mice were sacrificed on day 12, and tumor tissues were removed for mass cytometry assay. (F) Quantification of immune subsets in mass cytometry data in C1498FF–PD-1H tumors compared with C1498FF-mock tumors. n = 5 per group, P value determined by Student’s t test. Error bars represent SEM. *P < 0.05; **P < 0.01.