Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway

Yoshitaka Adachi (), Seitaro Terakura (), Masahide Osaki, Yusuke Okuno, Yoshitaka Sato, Ken Sagou, Yuki Takeuchi, Hirofumi Yokota, Kanae Imai, Peter Steinberger, Judith Leitner, Ryo Hanajiri, Makoto Murata and Hitoshi Kiyoi
Additional contact information
Yoshitaka Adachi: Nagoya University Graduate School of Medicine
Seitaro Terakura: Nagoya University Graduate School of Medicine
Masahide Osaki: Nagoya University Graduate School of Medicine
Yusuke Okuno: Nagoya City University Graduate School of Medical Sciences
Yoshitaka Sato: Nagoya University Graduate School of Medicine
Ken Sagou: Nagoya University Graduate School of Medicine
Yuki Takeuchi: Nagoya University Graduate School of Medicine
Hirofumi Yokota: Nagoya University Graduate School of Medicine
Kanae Imai: Nagoya University Graduate School of Medicine
Peter Steinberger: Medical University of Vienna
Judith Leitner: Medical University of Vienna
Ryo Hanajiri: Nagoya University Graduate School of Medicine
Makoto Murata: Nagoya University Graduate School of Medicine
Hitoshi Kiyoi: Nagoya University Graduate School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Chimeric antigen receptor (CAR) T cell is a promising therapy for cancer, but factors that enhance the efficacy of CAR T cell remain elusive. Here we perform a genome-wide CRISPR screening to probe genes that regulate the proliferation and survival of CAR T cells following repetitive antigen stimulations. We find that genetic ablation of CUL5, encoding a core element of the multi-protein E3 ubiquitin-protein ligase complex, cullin-RING ligase 5, enhances human CD19 CAR T cell expansion potential and effector functions, potentially via the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. In this regard, CUL5 knockout CD19 CAR T cells show sustained STAT3 and STAT5 phosphorylation, as well as delayed phosphorylation and degradation of JAK1 and JAK3. In vivo, shRNA-mediated knockdown of CUL5 enhances CD19 CAR T treatment outcomes in tumor-bearing mice. Our findings thus imply that targeting CUL5 in the ubiquitin system may enhance CAR T cell effector functions to enhance immunotherapy efficacy.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-54794-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54794-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-54794-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().