Enhancing Gamma Delta (γδ) T-Cell Therapies Through Engineered Biochemical and Mechanical Microenvironments
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Obuseh-fobuseh-PhD-HST-2026-thesis.pdf
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5.98 MB
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Author(s)
Obuseh, Favour Omafuvwe
Advisor(s)
Mooney, David J.
Date Issued
May 2026
Publisher
Massachusetts Institute of Technology
Abstract
Gamma delta (γδ) T-cells comprise approximately 0.5-10% of T-cells in human peripheral blood and have recently gained interest in the context of adoptive T-cell therapy. Notably, tumor-infiltrating γδ T-cells have been identified as a significant positive prognostic population, in some settings showing stronger associations with favorable outcomes than conventional CD8+ or CD4+ αβ T-cells, which have been the primary focus of most cell therapy approaches. Efforts to improve γδ T-cell expansion and cytotoxic function using cytokines, genetic engineering, and alternative activation models have yielded mixed results, in part because current expansion systems fail to recapitulate the mechanical and biochemical milieu encountered in vivo. Building on observations that tissue-resident γδ T-cells exhibit phenotypes distinct from those found in blood, we employed an engineered collagen matrix designed to recapitulate key tissue features, including viscoelasticity, in order to examine its effects on γδ T-cell differentiation, phenotype, and cytotoxic potential. Using this system, we identified tissue mechanics as a checkpoint in γδ T-cell biology and as a driver of distinct phenotypic and cytotoxic outcomes. To address persistent challenges in γδ T-cell expansion, we also developed a tunable alginate microgel system in which biochemical cues could be varied to determine how increased stimulation density influences γδ T-cell expansion and phenotype. This microgel platform further enabled us to investigate how prior antigen experience shapes γδ T-cell expansion potential and function.
MIT Department
Harvard-MIT Program in Health Sciences and Technology
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