PD-1 checkpoint blockade enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against human prostate cancer

被引:26
作者
Nada, Mohanad H. [1 ,2 ,3 ,4 ]
Wang, Hong [1 ,2 ]
Hussein, Auter J. [1 ,5 ]
Tanaka, Yoshimasa [6 ]
Morita, Craig T. [1 ,2 ,7 ]
机构
[1] Iowa City Vet Hlth Care Syst, Dept Vet Affairs, Iowa City, IA 52246 USA
[2] Univ Iowa Carver Coll Med, Dept Internal Med, Div Immunol, Iowa City, IA 52242 USA
[3] Tikrit Univ, Coll Med, Dept Pathol, Tikrit, Iraq
[4] Amer Univ Iraq, Dept Med & Hlth Sci, Sulaymaniah, Iraq
[5] Minist Hlth, Salah Al Din Directorate Hlth, Baghdad, Iraq
[6] Nagasaki Univ, Ctr Med Innovat, Nagasaki, Japan
[7] Univ Iowa Carver Coll Med, Interdisciplinary Grad Program Immunol, Iowa City, IA 52242 USA
基金
美国国家卫生研究院;
关键词
Adoptive immunotherapy; programed cell death 1 receptor; prostatic neoplasms; inhibitory T cell receptors; combined modality therapy; human gamma delta T cells; V gamma 2V delta 2 T cells; NONPEPTIDE ANTIGENS; ESTABLISHED TUMORS; BUTYROPHILIN; 3A1; PHASE-I; GAMMA; ZOLEDRONATE; RECOGNITION; EXPRESSION; LYMPHOCYTES; COMBINATION;
D O I
10.1080/2162402X.2021.1989789
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Human V gamma 2V delta 2 (also termed V gamma 9V delta 2) T cells play important roles in microbial and tumor immunity by monitoring foreign- and self-prenyl pyrophosphate metabolites in isoprenoid biosynthesis. Accumulation of isoprenoid metabolites after bisphosphonate treatment allows V gamma 2V delta 2 T cells to recognize and kill tumors independently of their MHC expression or burden of non-synonymous mutations. Clinical trials with more than 400 patients show that adoptive immunotherapy with V gamma 2V delta 2 T cells has few side effects but has resulted in only a few partial and complete remissions. Here, we have tested V gamma 2V delta 2 T cells for expression of inhibitory receptors and determined whether adding PD-1 checkpoint blockade to adoptively transferred V gamma 2V delta 2 T cells enhances immunity to human PC-3 prostate tumors in an NSG mouse model. We find that V gamma 2V delta 2 T cells express PD-1, CTLA-4, LAG-3, and TIM-3 inhibitory receptors during the 14-day ex vivo expansion period, and PD-1, LAG-3, and TIM-3 upon subsequent stimulation by pamidronate-treated tumor cells. Expression of PD-L1 on PC-3 prostate cancer cells was increased by co-culture with activated V gamma 2V delta 2 T cells. Importantly, anti-PD-1 mAb treatment enhanced V gamma 2V delta 2 T cell immunity to PC-3 tumors in immunodeficient NSG mice, reducing tumor volume nearly to zero after 5 weeks. These results demonstrate that PD-1 checkpoint blockade can enhance the effectiveness of adoptive immunotherapy with human gamma delta T cells in treating prostate tumors in a preclinical model.
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页数:17
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