Enhancing adoptive cancer immunotherapy with Vγ2Vδ2 T cells through pulse zoledronate stimulation

Autor: Hong Wang, Grefachew Workalemahu, Yoshimasa Tanaka, Craig T. Morita, Mohanad H. Nada
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Cancer Research
medicine.medical_treatment
Stimulation
Immunotherapy
Adoptive
Zoledronic Acid
Interleukin 21
Mice
0302 clinical medicine
Cancer immunotherapy
Neoplasms
Immunology and Allergy
Cytotoxic T cell
Intraepithelial Lymphocytes
Interleukin-15
Prostate cancer
Diphosphonates
Imidazoles
3. Good health
Tumor Burden
medicine.anatomical_structure
Oncology
IL-15
Interleukin 15
Adoptive cancer immunotherapy
Molecular Medicine
Female
medicine.drug
Research Article
Human
Zoledronate
Interleukin 2
Memory T cell subsets
Adult
T cell
Immunology
γδ T cells
03 medical and health sciences
Cell Line
Tumor
medicine
Bisphosphonate
Animals
Humans
Pharmacology
Vγ2Vδ2 T cells
business.industry
IL-2
030104 developmental biology
Humanized mouse
Cancer research
Interleukin-2
business
030215 immunology
Zdroj: Journal for Immunotherapy of Cancer
ISSN: 2051-1426
Popis: Background Human γδ T cells expressing Vγ2Vδ2 T cell receptors monitor foreign- and self-prenyl pyrophosphate metabolites in isoprenoid biosynthesis to mediate immunity to microbes and tumors. Adoptive immunotherapy with Vγ2Vδ2 T cells has been used to treat cancer patients with partial and complete remissions. Most clinical trials and preclinical studies have used continuous zoledronate exposure to expand Vγ2Vδ2 cells where zoledronate is slowly diluted over the course of the culture. Zoledronate inhibits farnesyl diphosphate synthase (FDPS) in monocytes causing isopentenyl pyrophosphate to accumulate that then stimulates Vγ2Vδ2 cells. Because zoledronate inhibition of FDPS is also toxic for T cells, we hypothesized that a short period of exposure would reduce T cell toxicity but still be sufficient for monocytes uptake. Additionally, IL-15 increases the anti-tumor activity of murine αβ T cells in mice but its effect on the in vivo anti-tumor activity of human Vγ2Vδ2 cells has not been assessed. Methods Human Vγ2Vδ2 T cells were expanded by pulse or continuous zoledronate stimulation with IL-2 or IL-15. Expanded Vγ2Vδ2 cells were tested for their expression of effector molecules and killing of tumor cells as well as their in vivo control of human prostate cancer tumors in immunodeficient NSG mice. Results Pulse zoledronate stimulation with either IL-2 or IL-15 resulted in more uniform expansion of Vγ2Vδ2 cells with higher purity and cell numbers as compared with continuous exposure. The Vγ2Vδ2 cells had higher levels of CD107a and perforin and increased tumor cytotoxicity. Adoptive immunotherapy with Vγ2Vδ2 cells derived by pulse stimulation controlled human PC-3 prostate cancer tumors in NSG mice significantly better than those derived by continuous stimulation, halting tumor growth. Although pulse zoledronate stimulation with IL-15 preserved early memory subsets, adoptive immunotherapy with IL-15-derived Vγ2Vδ2 cells equally inhibited PC-3 tumor growth as those derived with IL-2. Conclusions Pulse zoledronate stimulation maximizes the purity, quantity, and quality of expanded Vγ2Vδ2 cells for adoptive immunotherapy but there is no advantage to using IL-15 over IL-2 in our humanized mouse model. Pulse zoledronate stimulation is a simple modification to existing protocols that will enhance the effectiveness of adoptively transferred Vγ2Vδ2 cells by increasing their numbers and anti-tumor activity. Electronic supplementary material The online version of this article (doi:10.1186/s40425-017-0209-6) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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