Selective HLA knockdown and PD-L1 expression prevent allogeneic CAR-NK cell rejection and enhance safety and anti-tumor responses in xenograft mice

Fuguo Liu, Mubin Tarannum, Yingjie Zhao, Yiming J. Zhang, James Dongjoo Ham, Kewen Lei, Yuhao Qiang, Xingyu Deng, Maily Nguyen, Khanhlinh Dinh, Shaobo Yang, Alaa Kassim Ali, Toni K. Choueiri, Jerome Ritz, Rizwan Romee () and Jianzhu Chen ()
Additional contact information
Fuguo Liu: Massachusetts Institute of Technology
Mubin Tarannum: Harvard Medical School
Yingjie Zhao: Massachusetts Institute of Technology
Yiming J. Zhang: Massachusetts Institute of Technology
James Dongjoo Ham: Massachusetts Institute of Technology
Kewen Lei: Massachusetts Institute of Technology
Yuhao Qiang: Massachusetts Institute of Technology
Xingyu Deng: Harvard Medical School
Maily Nguyen: Harvard Medical School
Khanhlinh Dinh: Harvard Medical School
Shaobo Yang: Harvard Medical School
Alaa Kassim Ali: Harvard Medical School
Toni K. Choueiri: Harvard Medical School
Jerome Ritz: Harvard Medical School
Rizwan Romee: Harvard Medical School
Jianzhu Chen: Massachusetts Institute of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Allogeneic cellular immunotherapy exhibits promising efficacy for cancer treatment, but donor cell rejection remains a major barrier. Here, we systematically evaluate human leukocyte antigens (HLA) and immune checkpoints PD-L1, HLA-E, and CD47 in the rejection of allogeneic NK cells and identify CD8+ T cells as the dominant cell type mediating allorejection. We demonstrate that a single gene construct that combines an shRNA that selectively interferes with HLA class I but not HLA-E expression, a chimeric antigen receptor (CAR), and PD-L1 or single-chain HLA-E (SCE) enables the one-step construction of allogeneic CAR-NK cells that evade host-mediated rejection both in vitro and in a xenograft mouse model. Furthermore, CAR-NK cells overexpressing PD-L1 or SCE effectively kill tumor cells through the upregulation of cytotoxic genes and reduced exhaustion and exhibit a favorable safety profile due to the decreased production of inflammatory cytokines involved in cytokine release syndrome. Thus, our approach represents a promising strategy in enabling “off-the-shelf” allogeneic cellular immunotherapies.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63863-8 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:16:y:2025:i:1:d:10.1038_s41467-025-63863-8

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

DOI: 10.1038/s41467-025-63863-8

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 ().