Potentiating adoptive cell therapy using synthetic IL-9 receptors.

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. © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

Anusha Kalbasi, Mikko Siurala, Leon L Su, Mito Tariveranmoshabad, Lora K Picton, Pranali Ravikumar, Peng Li, Jian-Xin Lin, Helena Escuin-Ordinas, Tong Da, Sarah V Kremer, Amy L Sun, Sofia Castelli, Sangya Agarwal, John Scholler, Decheng Song, Philipp C Rommel, Enrico Radaelli, Regina M Young, Warren J Leonard, Antoni Ribas, Carl H June, K Christopher Garcia. Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature. 2022 Jul;607(7918):360-365

Mesh Tags

Substances

PMID: 35676488

search → result