학술논문
Potentiating adoptive cell therapy using synthetic IL-9 receptors
Document Type
article
Author
Kalbasi, Anusha; Siurala, Mikko; Su, Leon L; Tariveranmoshabad, Mito; Picton, Lora K; Ravikumar, Pranali; Li, Peng; Lin, Jian-Xin; Escuin-Ordinas, Helena; Da, Tong; Kremer, Sarah V; Sun, Amy L; Castelli, Sofia; Agarwal, Sangya; Scholler, John; Song, Decheng; Rommel, Philipp C; Radaelli, Enrico; Young, Regina M; Leonard, Warren J; Ribas, Antoni; June, Carl H; Garcia, K Christopher
Source
Nature. 607(7918)
Subject
Language
Abstract
Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD-IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.