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

Abstract

Human Vγ2Vδ2 (also termed Vγ9Vδ2) 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 Vγ2Vδ2 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 Vγ2Vδ2 T cells has few side effects but has resulted in only a few partial and complete remissions. Here, we have tested Vγ2Vδ2 T cells for expression of inhibitory receptors and determined whether adding PD-1 checkpoint blockade to adoptively transferred Vγ2Vδ2 T cells enhances immunity to human PC-3 prostate tumors in an NSG mouse model. We find that Vγ2Vδ2 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 Vγ2Vδ2 T cells. Importantly, anti-PD-1 mAb treatment enhanced Vγ2Vδ2 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 γδ T cells in treating prostate tumors in a preclinical model.

• Authors: Mohanad H Nada, Hong Wang, Auter J Hussein, Yoshimasa Tanaka, Craig T Morita
• Journal: Oncoimmunology (Oncoimmunology) Vol. 10 Issue 1 Pg. 1989789 ( 2021) ISSN: 2162-402X [Electronic] United States
• PMID: 34712512 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.

Chemical References

• Programmed Cell Death 1 Receptor
• Receptors, Antigen, T-Cell, gamma-delta

Topics

• Animals
• Humans
• Immunotherapy, Adoptive
• Lymphocyte Activation
• Male
• Mice
• Programmed Cell Death 1 Receptor
• Prostatic Neoplasms (drug therapy)
• Receptors, Antigen, T-Cell, gamma-delta
• T-Lymphocytes