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Potentiating adoptive cell therapy using synthetic IL-9 receptors
Anusha Kalbasi1,2, Mikko Siurala3,4, Leon L Su5
1Department of Radiation Oncology, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. anushakalbasi@mednet.ucla.edu.
Nature
|June 8, 2022
Summary
Engineered T cells with a novel chimeric receptor (o9R) show enhanced anti-tumour activity against solid tumours. This approach improves T cell function without requiring conditioning chemotherapy, offering new hope for cancer treatment.
Area of Science:
- Immunology
- Cancer Biology
- Synthetic Biology
Background:
- Adoptively transferred T cells face challenges in treating solid tumours, often necessitating conditioning chemotherapy.
- Synthetic receptor signaling offers a strategy to engineer T cells with novel anti-tumour functions.
Purpose of the Study:
- To design chimeric receptors that enable T cells to signal through orthogonal cytokine pathways.
- To evaluate the anti-tumour efficacy of T cells engineered with a specific chimeric receptor (o9R) in solid tumour models.
Main Methods:
- Construction of chimeric receptors by fusing the IL-2 receptor extracellular domain (ECD) with intracellular domains (ICD) of common γ-chain (γc) cytokine receptors.
- Analysis of T cell signaling pathways (STAT1, STAT3, STAT5) activated by chimeric receptors.
- Assessment of anti-tumour efficacy of engineered T cells in syngeneic mouse models of melanoma and pancreatic cancer, with and without lymphodepletion.
Main Results:
- T cells engineered with the o9R chimeric receptor exhibited concomitant activation of STAT1, STAT3, and STAT5.
- o9R T cells displayed characteristics of stem cell memory and effector T cells.
- o9R T cells demonstrated superior anti-tumour efficacy compared to o2R T cells in melanoma and pancreatic cancer models, even without conditioning chemotherapy.
Conclusions:
- Repurposing IL-9 receptor signaling via a chimeric orthogonal cytokine receptor enhances T cell function.
- Engineered T cells (o9R) provide improved anti-tumour activity against challenging solid tumours.
- This synthetic biology approach offers a promising strategy for T cell-based cancer immunotherapy, potentially obviating the need for lymphodepletion.
