Journal article
FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy
Jack D Chan, Christina M Scheffler, Isabelle Munoz, Kevin Sek, Joel N Lee, Yu-Kuan Huang, Kah Min Yap, Nicole YL Saw, Jasmine Li, Amanda XY Chen, Cheok Weng Chan, Emily B Derrick, Kirsten L Todd, Junming Tong, Phoebe A Dunbar, Jiawen Li, Thang X Hoang, Maria N de Menezes, Emma V Petley, Joelle S Kim Show all
Nature | Nature Research | Published : 2024
Abstract
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1,2,3,4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more ‘stem-like’ phenotype and increased mitochondrial mass6,7,8. We therefore sought to identify transcription factors that could enhance CAR T c..
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Grants
Awarded by National Health and Medical Research Council (NHMRC)
Awarded by National Breast Cancer Foundation
Awarded by National Breast Cancer Foundation Fellowship
Awarded by Victorian Cancer Agency Early Career Fellowship
Awarded by NHMRC Senior Research Fellowships
Awarded by US Cancer Research Institute Irvington postdoctoral fellowship
Awarded by NHMRC
Awarded by Victorian Cancer Agency
Funding Acknowledgements
This work was funded by a programme grant and ideas grant from the National Health and Medical Research Council (NHMRC programme grant number 1132373, ideas grant 2012475 and a project grant from the National Breast Cancer Foundation (IIRS-22-095). P.A.B. was supported by a National Breast Cancer Foundation Fellowship (ECF-17-005, 2017- 2020) and a Victorian Cancer Agency Mid-Career Fellowship (MCRF20011, 2021-current). I.G.H. was supported by a Victorian Cancer Agency Early Career Fellowship (ECRF20017). P.K.D. was supported by NHMRC Senior Research Fellowships (APP1136680 (2018-2022) and 2026403 (2024-current)). J. Lai was a recipient of a US Cancer Research Institute Irvington postdoctoral fellowship (award no. 3530). I.A.P. was supported by a Victorian Cancer Agency Mid-Career Fellowship (2022- Current). A.M.S. was supported by an NHMRC Investigator Fellowship (1177837). C.Y.S. was supported by a mid-career Fellowship from the Victorian Cancer Agency (MCRF22022). The authors acknowledge the contributions of K. Gill, M. Rear and G. Sissing who act as consumer representatives for the laboratory, the Peter MacCallum Molecular Genomics, Flow Cytometry, Genotyping and Animal Facility Cores for their respective contributions to the study. The authors thank the Centre of Excellence in Cellular Immunotherapy at the Peter MacCallum Cancer Centre for supply of the lentiviral plasmid. Images in Fig. 1a and Extended Data Fig. 3a were created with BioRender.com.