A genome-scale screen for synthetic drivers of T cell proliferation

Mateusz Legut (), Zoran Gajic, Maria Guarino, Zharko Daniloski, Jahan A. Rahman, Xinhe Xue, Congyi Lu, Lu Lu, Eleni P. Mimitou, Stephanie Hao, Teresa Davoli, Catherine Diefenbach, Peter Smibert and Neville E. Sanjana ()
Additional contact information
Mateusz Legut: New York Genome Center
Zoran Gajic: New York Genome Center
Maria Guarino: New York Genome Center
Zharko Daniloski: New York Genome Center
Jahan A. Rahman: New York Genome Center
Xinhe Xue: New York Genome Center
Congyi Lu: New York Genome Center
Lu Lu: New York Genome Center
Eleni P. Mimitou: New York Genome Center
Stephanie Hao: New York Genome Center
Teresa Davoli: New York University School of Medicine
Catherine Diefenbach: New York University School of Medicine
Peter Smibert: New York Genome Center
Neville E. Sanjana: New York Genome Center

Nature, 2022, vol. 603, issue 7902, 728-735

Abstract: Abstract The engineering of autologous patient T cells for adoptive cell therapies has revolutionized the treatment of several types of cancer1. However, further improvements are needed to increase response and cure rates. CRISPR-based loss-of-function screens have been limited to negative regulators of T cell functions2–4 and raise safety concerns owing to the permanent modification of the genome. Here we identify positive regulators of T cell functions through overexpression of around 12,000 barcoded human open reading frames (ORFs). The top-ranked genes increased the proliferation and activation of primary human CD4+ and CD8+ T cells and their secretion of key cytokines such as interleukin-2 and interferon-γ. In addition, we developed the single-cell genomics method OverCITE-seq for high-throughput quantification of the transcriptome and surface antigens in ORF-engineered T cells. The top-ranked ORF—lymphotoxin-β receptor (LTBR)—is typically expressed in myeloid cells but absent in lymphocytes. When overexpressed in T cells, LTBR induced profound transcriptional and epigenomic remodelling, leading to increased T cell effector functions and resistance to exhaustion in chronic stimulation settings through constitutive activation of the canonical NF-κB pathway. LTBR and other highly ranked genes improved the antigen-specific responses of chimeric antigen receptor T cells and γδ T cells, highlighting their potential for future cancer-agnostic therapies5. Our results provide several strategies for improving next-generation T cell therapies by the induction of synthetic cell programmes.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04494-7 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

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:nature:v:603:y:2022:i:7902:d:10.1038_s41586-022-04494-7

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

DOI: 10.1038/s41586-022-04494-7

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

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