Dichotomous and stable gamma delta T-cell number and function in healthy individuals

Document Type

Article

Publication Date

5-19-2021

Abstract

Background Gamma-delta ( 3δ) T lymphocytes are primed to potently respond to pathogens and transformed cells by recognizing a broad range of antigens. However, adoptive immunotherapy with 3δ T cells has exhibited mixed treatment responses. Better understanding of 3δ T cell biology and stratifying healthy donors for allogeneic adoptive therapy is clinically needed to fully realize the therapeutic potential of 3δ T cells. Methods We examine 98 blood samples from healthy donors and measure their expansion capacity after zoledronate stimulation, and test the migration and cytotoxic effector function of expanded 3δ T cells in 2D culture, 3D tumor spheroid and patient-derived melanoma organoid assays. Results We find that 3δ T cell expansion capacity is independent of expansion methods, gender, age and HLA type. Basal 3δ T cell levels in Peripheral blood mononuclear cell (PBMC) correlate well with their expansion, migration and cytotoxic effector capacity in vitro. Circulating 3δ T cells with lower expression of PD-1, CTLA-4, Eomes, T-bet and CD69, or higher IFN-γproduction expand better. 3δ T cells with central memory and effector memory phenotypes are significantly more abundant in good expanders. A cut-off level of 0.82% 3δ T cells in PBMC stratifies good versus poor 3δ T cell expansion with a sensitivity of 97.78%, specificity of 90.48% and area under the curve of 0.968 in a healthy individual. Donors with higher Vδ 2 Index Score in PBMC have greater anti-tumor functions including migratory function and cytotoxicity. Conclusions Our results demonstrate that the interindividual 3δ T cell functions correlate with their circulating levels in healthy donors. Examination of circulating 3δ T cell level may be used to select healthy donors to participate in 3δ T-based immunotherapies.

Identifier

85106581302 (Scopus)

Publication Title

Journal for Immunotherapy of Cancer

External Full Text Location

https://doi.org/10.1136/jitc-2020-002274

e-ISSN

20511426

PubMed ID

34011536

Issue

5

Volume

9

Grant

CA170340

Fund Ref

National Institutes of Health

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