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 4

Anti-mouse PD-1H mAb reverses immune evasion induced by mouse AML surface PD-1H.

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Anti-mouse PD-1H mAb reverses immune evasion induced by mouse AML surfac...
(A) PD-1H suppressed T cell activation. Inhibition of OT-1 T cells by mouse PD-1H on 293-KbOVA cells. T cell proliferation was assessed by CFSE dilution. The diluted population was assessed by the percentage of total T cells. (B and C) B6 PD-1H–KO mice were transplanted with myeloid leukemia cells expressing full-length PD-1H (C1498FF–PD-1H FL) and treated with anti–mPD-1H mAb (13F3) (B). Mice were assessed for in vivo leukemia proliferation using bioluminescence (C). A total of 200 μg of 13F3 or isotype control mAb was i.p. injected every 4 days from day 1 of transplantation of C1498FF–PD-1H cells (total 4 doses). 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. *P < 0.05. (D–F) In vivo growth of C1498FF–PD-1H s.c. tumor in B6 WT mice following anti–mPD-1H mAb treatment. A total of 200 μg of 13F3 or isotype control mAb was i.p. injected every 4 days from day 0 after s.c. injection of C1498FF–PD-1H cells (total 3 doses). (D) Tumor size was significantly smaller in the 13F3 treatment group compared with the isotype treatment group. Mean tumor volume ± SEM. Error bars represent SEM. n = 6 per group. *P < 0.05. (E and F) C1498FF–PD-1H s.c. tumor growth with 13F3 or isotype mAb treatment in B6 WT mice depleted of T cells or NK cells. n = 6. *P <0.05; ***P <0.01. P value determined by Student’s t test at each time point. (G) Immune cell subsets infiltrated in C1498FF–PD-1H tumors were assessed using mass cytometry. Left: percentages of granzyme B+ CD8+ T cells in total CD8+ T cells. Right: percentages of effector memory phenotype (CD44+CD62L–) CD8+ T cells in total CD8+ T cells. P value determined by Student’s t test. Error bars represent SEM. *P <0.05; **P <0.01.