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Ablation of T cell–associated PD-1H enhances functionality and promotes adoptive immunotherapy
Li Hu, … , Gangxiong Huang, Lieping Chen
Li Hu, … , Gangxiong Huang, Lieping Chen
Published December 14, 2021
Citation Information: JCI Insight. 2022;7(2):e148247. https://doi.org/10.1172/jci.insight.148247.
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Research Article Immunology Therapeutics

Ablation of T cell–associated PD-1H enhances functionality and promotes adoptive immunotherapy

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Abstract

Programmed death-1 homolog (PD-1H) is a coinhibitory molecule that negatively regulates T cell–mediated immune responses. In this study, we determined whether ablation of T cell–associated PD-1H could enhance adoptive T cell therapy in experimental tumor models. The expression of PD-1H is upregulated in activated and tumor-infiltrating CD8+ T cells. Activated CD8+ T cells from PD-1H–deficient (PD-1H–KO) mice exhibited increased cell proliferation, cytokine production, and antitumor activity in vitro. Adoptive transfer of PD-1H–KO CD8+ T cells resulted in the regression of established syngeneic mouse tumors. Similar results were obtained when PD-1H was ablated in T cells by CRISPR/Cas9-mediated gene silencing. Furthermore, ablation of PD-1H in CAR-T cells significantly improved their antitumor activity against human xenografts in vivo. Our results indicate that T cell–associated PD-1H could suppress immunity in the tumor microenvironment and that targeting PD-1H may improve T cell adoptive immunotherapy.

Authors

Li Hu, Ling Chen, Zexiu Xiao, Xu Zheng, Yuangui Chen, Na Xian, Christina Cho, Liqun Luo, Gangxiong Huang, Lieping Chen

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Figure 1

Upregulation of PD-1H expression is maintained on activated T cells.

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Upregulation of PD-1H expression is maintained on activated T cells.
(A ...
(A and B) Tumor cells were inoculated into the flank of WT mice (n = 4 for B16-OVA; n = 5 for EG7 group). Tumors were harvested when the tumor reaches 10–15 mm. Expression of PD-1H on spleen and TILs, including CD4+ and CD8+ T cells, was analyzed by flow cytometry. Data are representative of 3 independent experiments with mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001 (2-tailed unpaired t test). (C) The percentage of PD-1H expression on CD8+ T cells. WT or PK CD8+ T cells were either freshly isolated and in vitro culture for 3, 5, 14 days, with and without activation (1 μg/mL anti-mCD3 plus 2 μg/mL anti-mCD28). The expression of PD-1H on CD8+ T cells was analyzed by flow cytometry at days 3, 5, 14, and 17. (D) In total, 3 × 106/mL activated PD-1H+ CD8+ T cells were diluted in culture in vitro in a 96 well-plate; PD-1H expression was detected at 24, 48, and 72 hours by flow cytometry. Data are presented as mean ± SEM and represent 3 independent experiments. ****P < 0.0001 (2-way ANOVA).

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