Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion

S. Fiorenza (), Y. Zheng, J. Purushe, T. J. Bock, J. Sarthy, D. H. Janssens, A. S. Sheih, E. L. Kimble, D. Kirchmeier, T. D. Phi, J. Gauthier, A. V. Hirayama, S. R. Riddell, Q. Wu, R. Gottardo, D. G. Maloney, J. Y. H. Yang, S. Henikoff and C. J. Turtle
Additional contact information
S. Fiorenza: The University of Sydney
Y. Zheng: Fred Hutchinson Cancer Center
J. Purushe: Fred Hutchinson Cancer Cente
T. J. Bock: The University of Sydney
J. Sarthy: Fred Hutchinson Cancer Cente
D. H. Janssens: Fred Hutchinson Cancer Center
A. S. Sheih: Fred Hutchinson Cancer Cente
E. L. Kimble: Fred Hutchinson Cancer Cente
D. Kirchmeier: Fred Hutchinson Cancer Cente
T. D. Phi: Fred Hutchinson Cancer Cente
J. Gauthier: Fred Hutchinson Cancer Cente
A. V. Hirayama: Fred Hutchinson Cancer Cente
S. R. Riddell: Fred Hutchinson Cancer Cente
Q. Wu: Fred Hutchinson Cancer Cente
R. Gottardo: Lausanne University Hospital
D. G. Maloney: Fred Hutchinson Cancer Cente
J. Y. H. Yang: The University of Sydney
S. Henikoff: Fred Hutchinson Cancer Center
C. J. Turtle: The University of Sydney

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionised blood cancer treatment. Parsing the genetic underpinnings of T cell quality and CAR-T efficacy is challenging. Transcriptomics inform CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasises effector and metabolism genes. Here we explore whether analyses of transcriptionally repressive and permissive histone methylation marks describe CAR-T cell functional states and therapeutic potential beyond transcriptomic analyses. Histone mark analyses improve identification of differences between naïve, central memory, and effector memory CD8 + T cell subsets of human origin, and CAR-T derived from these subsets. We find important differences between CAR-T manufactured from central memory cells of healthy donors and of patients. By examining CAR-T products from a clinical trial in lymphoma (NCT01865617), we find a novel association between the activity of the transcription factor KLF7 with in vivo CAR-T accumulation in patients and demonstrate that over-expression of KLF7 increases in vitro CAR-T proliferation and IL-2 production. In conclusion, histone marks provide a rich dataset for identification of functionally relevant genes not apparent by transcriptomics.

Date: 2024
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DOI: 10.1038/s41467-024-52503-2

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