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

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.

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Publication Details

Journal
Nature Communications
Published
2024-12-10
DOI
https://doi.org/10.1038/s41467-024-54794-x
Citations
13
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
3.67

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article

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

Yoshitaka Sato, Hitoshi Kiyoi, Ken Sagou, Makoto Murata et al.
13 citations
Nature Communications
CAR-T cell therapy research
3.67
article

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

Yoshitaka Sato, Hitoshi Kiyoi, Ken Sagou, Makoto Murata, Seitaro Terakura, Yusuke Okuno, Yuki Takeuchi, Hirofumi Yokota, Peter Steinberger, Masahide Osaki, Kanae Imai, Ryo Hanajiri, Judith Leitner, Yoshitaka Adachi
article en
13 citations

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.

Nature CommunicationsVol. 15(1)
Nagoya City University (JP), Nagoya University Hospital (JP), Nagoya University (JP), Medical University of Vienna (AT)
Japan Society for the Promotion of Science, Japan Science and Technology Agency, Core Research for Evolutional Science and Technology
Openalex Percentile: Top 5%
CAR-T cell therapy research
3.67
DOIOpen Access PDFOpenAlex
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