免疫系をプログラミングし、がん細胞治療を強化する(Programming the Immune System to Supercharge Cancer Cell Therapies)

2022-03-16 ニューヨーク大学

• https://www.nyu.edu/about/news-publications/news/2022/march/programming-the-immune-system-to-supercharge-cancer-cell-therapi.html
• https://www.nature.com/articles/s41586-022-04494-7

T細胞増殖の合成ドライバーを探索するゲノムスケールスクリーン 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 & Neville E. Sanjana

Nature (2022)Cite this article　213 Altmetric　Metricsdetails

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 functions^2,3,4 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.