- 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
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.