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Non-Viral Engineering of Primary Human T Cells via Homology-Mediated End-Joining Targeted Integration of Large DNA Templates
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Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against
Konstantinos Lontos1, Yiyang Wang1,2, Supriya K Joshi1
1Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA.
Journal for Immunotherapy of Cancer
|March 13, 2023
Summary
Metabolic reprogramming of chimeric antigen receptor (CAR)-T cells using PGC-1α enhances mitochondrial biogenesis and effector functions. This approach improves CAR-T cell efficacy in solid tumors, offering a promising strategy for cancer immunotherapy.
Area of Science:
- Immunology
- Metabolic Engineering
- Oncology
Background:
- Chimeric antigen receptor (CAR)-T cell therapy shows promise in blood cancers but faces resistance in solid tumors due to the tumor microenvironment and T cell metabolic deficiencies.
- T cell differentiation within tumors can lead to impaired mitochondrial biogenesis and cell-intrinsic metabolic deficits, hindering anti-tumor activity.
- Previous studies demonstrated improved murine T cell receptor (TCR)-transgenic cells via enhanced mitochondrial biogenesis.
Purpose of the Study:
- To investigate whether metabolic reprogramming can enhance human CAR-T cells for solid tumor treatment.
- To determine if an engineered version of PGC-1α can overcome metabolic barriers and improve CAR-T cell function.
Main Methods:
- Human anti-EGFR CAR-T cells were co-transduced with lentiviruses encoding PGC-1α, a mutant PGC-1α (PGC-1αS571A), or a truncated version (NT-PGC-1α).
- Metabolic reprogramming was assessed using in vitro flow cytometry, Seahorse analysis, and RNA sequencing.
- Therapeutic efficacy was evaluated in NSG mice bearing human A549 solid tumors treated with engineered CAR-T cells.
Main Results:
- Engineered PGC-1α successfully reprogrammed human CAR-T cells, inducing mitochondrial biogenesis and upregulating effector function programs.
- Treatment with PGC-1α-modified CAR-T cells significantly improved anti-tumor efficacy in a murine model of human solid tumors.
- A truncated version, NT-PGC-1α, did not yield similar improvements in in vivo anti-tumor outcomes.
Conclusions:
- Metabolic reprogramming using PGC-1α is a viable strategy to enhance CAR-T cell function and overcome resistance in solid tumors.
- PGC-1α represents a promising therapeutic target for improving cell-based immunotherapies for solid tumors.
- Further research into PGC-1α and similar metabolic regulators could lead to more effective cell therapies for various cancers.
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