MEMP PhD Thesis Defense: Favour Obuseh

Enhancing Gamma Delta (γδ) T-Cell Therapies Through Engineered Biochemical and Mechanical Microenvironments

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 viscoelasticity, a key feature of tissues, to examine its effects on γδ T-cell differentiation, phenotype, and cytotoxic potential. Using this system, we identified viscoelasticity as a modulator of 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 surface presentation of 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. Altogether, this thesis demonstrates that engineering biochemical and mechanical environments that recapitulate in vivo γδ T-cell niches is essential for maximizing expansion potential and improving efficacy in the context of cancer immunotherapy.

Thesis Supervisor:
David J Mooney, PhD 
Robert P. Pinkas Family Professor of Bioengineering, Harvard John A. Paulson School of Engineering and Applied Science

Thesis Committee Chair:
Sangeeta Bhatia, MD, PhD 
John J. and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science, MIT

Thesis Reader:
Kai Wucherpfennig, MD, PhD 
Chair, Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute
Nancy Lurie Marks Professor of Neurology in the field of Medical Oncology, Harvard Medical School
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Topic: Favour Obuseh MEMP PhD Thesis Defense
Time: Monday, May 4, 2026, 9:00 AM Eastern Time (US and Canada)

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