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Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma
Nicolas Jacquelot1,2,3, Cyril Seillet4,5, Minyu Wang6,7
1The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. nicolas.jacquelot@uhnresearch.ca.
Abstract:
Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
Insights
High infiltration of group 2 innate lymphoid cells (ILC2s) in melanoma predicts a good prognosis. Activating ILC2s alongside blocking programmed cell death protein-1 (PD-1) enhances anti-melanoma immune responses.
Area of Science:
- Immunology
- Oncology
Background:
- Group 2 innate lymphoid cells (ILC2s) play a dual role in cancer, with their specific functions in melanoma largely unknown.
- Understanding ILC2 mechanisms in cancer is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of ILC2s in human melanoma immunity.
- To explore the potential of targeting ILC2s for melanoma immunotherapy.
Main Methods:
- Analysis of ILC2 infiltration in human melanoma tissues.
- Assessment of ILC2-derived cytokine production (GM-CSF).
- Evaluation of programmed cell death protein-1 (PD-1) expression on tumor-infiltrating ILC2s.
- In vivo studies combining IL-33 activation and PD-1 blockade.
Main Results:
- High ILC2 infiltration in melanoma correlates with favorable clinical outcomes.
- ILC2s produce GM-CSF, promoting eosinophil recruitment and antitumor activity.
- PD-1 expression on ILC2s restricts their anti-tumor functions.
- Combined IL-33 activation and PD-1 blockade synergistically enhance anti-melanoma responses.
Conclusions:
- ILC2s are key players in anti-melanoma immunity.
- Targeting ILC2s, particularly in combination with PD-1 blockade, represents a promising therapeutic avenue for melanoma.
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