A genome-scale screen for synthetic drivers of T cell proliferation
Mateusz Legut,Zoran Gajic,Maria Francesca Guarino,Zharko Daniloski,J. Rahman,Xinhe Xue,Congyi Lu,Lu Lu,Eleni P. Mimitou,Stephanie Hao,Teresa Davoli,Catherine Diefenbach,Peter Smibert,Neville E. Sanjana +13 more
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TLDR
In this paper , the authors identify positive regulators of T cell functions through overexpression of around 12,000 barcoded human open reading frames (ORFs), which increased the proliferation and activation of primary human CD4+ and CD8+ T cells and their secretion of key cytokines such as interleukin-2 and interferonγ.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. A genome-scale gain-of-function screen using overexpression of nearly 12,000 open reading frames (ORFs) identifies positive regulators of human T cell function and suggests that ORF-based screens could be applied clinically to improve T cell therapies. read more
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Natural killer cells in antitumour adoptive cell immunotherapy
TL;DR: In this article , the authors describe various approaches to augment NK cell cytotoxicity and longevity, evaluate challenges and opportunities, and reflect on how lessons learned from the clinic will guide the design of next-generation NK cell products that will address the unique complexities of each cancer.
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Clinical implications of T cell exhaustion for cancer immunotherapy
TL;DR: Evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control is reviewed, and it is hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence.
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Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer
TL;DR: The recent US Food and Drug Administration approval of atezolizumab in combination with the chemotherapeutic agent nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced, or metastatic TNBC has led to a new era of immunotherapy in TNBC treatment and immunotherapy becomes an active research area.
Journal ArticleDOI
Multiplex base- and prime-editing with drive-and-process CRISPR arrays
Qichen Yuan,Xue Gao +1 more
TL;DR: In this paper , a drive-and-process (DAP) CRISPR array architectures for multiplex base-editing (MBE) and multiplex prime editing (MPE) in human cells is described.
Journal ArticleDOI
A T cell resilience model associated with response to immunotherapy in multiple tumor types
Yu Zhang,Trang Lan Vu,Douglas C. Palmer,Rigel J. Kishton,Lanqi Gong,Jiao Ren Huang,Thanh Nguyen,Zuojia Chen,Cari Smith,Ferenc Livak,Rohit Paul,Chi-Ping Day,Chuan Wu,G. Merino,Kenneth Aldape,Xin Yuan Guan,Peng Jiang +16 more
TL;DR: Tres (tumor-resilient T cell) as discussed by the authors is a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as transforming growth factor-β1, tumor necrosis factor-related apoptosisinducing ligand and prostaglandin E2.
References
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