Sarah McPhedran

Topic

Uncovering novel metabolic regulators of T cell function

School of Molecular Life Sciences

Date & location

• Monday, October 26, 2026

• 9:00 A.M.

• Clearihue Building, Room B017

Examining Committee

Supervisory Committee

• Dr. Julian Lum, School of Molecular Life Sciences, University of Victoria (Supervisor)

• Dr. Caroline Cameron, School of Molecular Life Sciences, UVic (Member)

• Dr. John Burke, School of Molecular Life Sciences, UVic (Member)

• Dr. Gregory Owens, Department of Biology, UVic (Outside Member) 

External Examiner

• Dr. Laura Evgin, Department of Medical Genetics, University of British Columbia 

Chair of Oral Examination

• Dr. Aloysius Maduforo, Department of Educational Psychology and Leadership Studies, UVic 

Abstract

T cell-based immunotherapies have transformed the treatment of hematological malignancies but remain largely ineffective against solid tumors, in part because of the metabolically suppressive tumor microenvironment (TME). To identify metabolic regulators of human T cell function under clinically relevant suppressive conditions, we developed a pooled CRISPR-Cas9 knockout screening platform using primary human T cells cultured in patient-derived high-grade serous carcinoma (HGSC) ascites. Using interferon-γ (IFN-γ) production and mitochondrial membrane potential as orthogonal functional readouts, we identified PRDX1 as a negative regulator of T cell effector function. Targeted deletion of PRDX1 increased the frequency of IFN-γ-producing T cells, enhanced glucose uptake, increased mitochondrial mass, and improved T cell viability under suppressive ascites conditions. Mechanistically, PRDX1 deletion increased intracellular reactive oxygen species (ROS) and impaired autophagic flux, implicating redox homeostasis and autophagy in regulating T cell function. Although PRDX1 deletion enhanced aspects of T cell function, its effects on chimeric antigen receptor (CAR)-T cell cytotoxicity were donor dependent, highlighting the importance of human biological heterogeneity and demonstrating that improvements in conventional T cell function do not necessarily translate to enhanced engineered T cell activity. Collectively, this study establishes a physiologically relevant human CRISPR screening platform for identifying metabolic regulators of T cell function within an ovarian cancer microenvironment and identifies PRDX1 as a context-dependent regulator of T cell activation, metabolism, and effector function.