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PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function
Matteo Morotti1,2,3, Alizee J Grimm1,2,3, Helen Carrasco Hope1,2
1Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland.
Nature
|April 24, 2024
Summary
Prostaglandin E2 (PGE2) impairs T cell function in the tumor microenvironment by blocking IL-2 signaling. Inhibiting PGE2 enhances T cell expansion and anti-tumor responses, improving adoptive cell therapy efficacy.
Area of Science:
- Immunology
- Cancer Biology
- Cell Therapy
Background:
- Tumor-infiltrating lymphocytes (TILs) are crucial for adoptive cell therapy (ACT) success.
- Interleukin-2 (IL-2) is vital for CD8+ T cell expansion and anti-tumor activity.
- Understanding IL-2 signaling barriers in the tumor microenvironment is key to enhancing T cell responses.
Purpose of the Study:
- To investigate the mechanisms by which prostaglandin E2 (PGE2) impairs IL-2 sensing in human CD8+ TILs.
- To explore the therapeutic potential of inhibiting PGE2 signaling in TIL expansion for ACT.
Main Methods:
- Analysis of PGE2 concentrations in patient tumor tissues.
- Assessment of IL-2 sensing in human CD8+ TILs exposed to PGE2.
- Investigation of molecular mechanisms involving IL-2 receptor gamma chain (IL-2Rγc) downregulation.
- Evaluation of PGE2 signaling inhibition on TIL proliferation and anti-tumor activity in vivo.
Main Results:
- High PGE2 concentrations in tumors impair IL-2 sensing in CD8+ TILs via EP2 and EP4 receptors.
- PGE2 downregulates IL-2Rγc, leading to defective IL-2 receptor assembly and impaired IL-2-mTOR signaling.
- This results in oxidative stress, ferroptotic cell death, and reduced anti-tumor function of TILs.
- Inhibition of PGE2-EP2/EP4 signaling enhances TIL proliferation and improves tumor control after ACT.
Conclusions:
- PGE2 is a significant barrier to IL-2 sensing and TIL function in the tumor microenvironment.
- Targeting PGE2 signaling offers a promising strategy to reinvigorate TILs for enhanced cancer immunotherapy.
- This approach can improve the expansion and therapeutic potential of effector T cells in ACT.
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