Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs

• 成果类型: Article
• 署名作者: Reddy, Nishith R.; Maachi, Hasna; Xiao, Yini; Simic, Milos S.; Yu, Wei; Tonai, Yurie; Cabanillas, Daniela A.; Serrano-Wu, Ella; Pauerstein, Philip T.; Tamaki, Whitney; Allen, Greg M.; Parent, Audrey V.; Hebrok, Matthias; Lim, Wendell A.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; Technical University of Munich; Technical University of Munich; German Center for Diabetes Research (DZD)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13804
• DOI: 10.1126/science.adl4793
• 发表日期: 2024-12-06
• 关键词: immune cells; immunotherapy; RECOGNITION; CHALLENGES; cancer

摘要

Immune homeostasis requires a balance of inflammatory and suppressive activities. To design cells potentially useful for local immune suppression, we engineered conventional CD4+ T cells with synthetic Notch (synNotch) receptors driving antigen-triggered production of anti-inflammatory payloads. Screening a diverse library of suppression programs, we observed the strongest suppression of cytotoxic T cell attack by the production of both anti-inflammatory factors (interleukin-10, transforming growth factor-beta 1, programmed death ligand 1) and sinks for proinflammatory cytokines (interleukin-2 receptor subunit CD25). Engineered cells with bespoke regulatory programs protected tissues from immune attack without systemic suppression. Synthetic suppressor T cells protected transplanted beta cell organoids from cytotoxic T cells. They also protected specific tissues from unwanted chimeric antigen receptor (CAR) T cell cross-reaction. Synthetic suppressor T cells are a customizable platform to potentially treat autoimmune diseases, organ rejection, and CAR T cell toxicities with spatial precision.