Reducing farnesyl diphosphate synthase levels activates Vγ9Vδ2 T cells and improves tumor suppression in murine xenograft cancer models.

Abstract

Human Vγ9Vδ2 T cells are attractive candidates for cancer immunotherapy due to their potent capacity for tumor recognition and cytolysis of many tumor cell types. However, efforts to deploy clinical strategies for Vγ9Vδ2 T cell cancer therapy are hampered by insufficient potency. We are pursuing an alternate strategy of modifying tumors to increase the capacity for Vγ9Vδ2 T cell activation, as a means for strengthening the anti-tumor response by resident or ex vivo manufactured Vγ9Vδ2 T cells. Vγ9Vδ2 T cells are activated in vitro by non-peptidic antigens including isopentenyl pyrophosphate (IPP), a substrate of farnesyl diphosphate synthase (FDPS) in the pathway for biosynthesis of isoprenoids. In an effort to improve in vivo potency of Vγ9Vδ2 T cells, we reduced FDPS expression in tumor cells using a lentivirus vector encoding a short-hairpin RNA that targets FDPS mRNA (LV-shFDPS). Prostate (PC3) or hepatocellular carcinoma (Huh-7) cells transduced with LV-shFDPS induced Vγ9Vδ2 T cell stimulation in vitro, resulting in increased cytokine expression and tumor cell cytotoxicity. Immune deficient mice implanted with LV-shFDPS transduced tumor cells showed dramatic responses to intraperitoneal injection of Vγ9Vδ2 T cells with strong suppression of tumor growth. In vivo potency was increased by transducing tumor cells with a vector expressing both shFDPS and human IL-2. Tumor suppression by Vγ9Vδ2 T cells was dose-dependent with greater effects observed in mice injected with 100% LV-shFDPS transduced cells compared to mice injected with a mixture of 50% LV-shFDPS transduced cells and 50% control (no vector) tumor cells. Delivery of LV-shFDPS by intratumoral injection was insufficient to knockdown FDPS in the majority of tumor cells, resulting in insignificant tumor suppression by Vγ9Vδ2 T cells. Thus, Vγ9Vδ2 T cells efficiently targeted and suppressed tumors expressing shFDPS in mouse xenotransplant models. This proof-of-concept study demonstrates the potential for suppression of genetically modified tumors by human Vγ9Vδ2 T cells and indicates that co-expression of cytokines may boost the anti-tumor effect.

• Authors: Mei-Ling Liou, Tyler Lahusen, Haishan Li, Lingzhi Xiao, C David Pauza
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 1012051 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 36275712 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Liou, Lahusen, Li, Xiao and Pauza.

Chemical References

• Geranyltranstransferase
• Receptors, Antigen, T-Cell, gamma-delta
• Interleukin-2
• RNA, Messenger
• RNA

Topics

• Male
• Humans
• Mice
• Animals
• T-Lymphocytes
• Geranyltranstransferase (genetics, pharmacology)
• Receptors, Antigen, T-Cell, gamma-delta (metabolism)
• Interleukin-2 (pharmacology)
• Heterografts
• Carcinoma, Hepatocellular
• Liver Neoplasms
• RNA, Messenger
• RNA