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ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity
John Alec Moral1,2,3, Joanne Leung1,2,3, Luis A Rojas1,2,3
1Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract:
Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues1,2. Although ILC2s are found in cancers of these tissues3, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8+ T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1+ TILC2s and PD-1+ T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.
Insights
Group 2 innate lymphoid cells (ILC2s) enhance pancreatic cancer immunity by activating anti-tumor responses. Blocking PD-1 on these cells boosts their anti-cancer activity, improving immunotherapy outcomes.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Group 2 innate lymphoid cells (ILC2s) are key regulators of tissue immunity.
- The role of ILC2s in cancer immunity and immunotherapy remains largely undefined.
- ILC2s have been observed in various tumor tissues, including pancreatic cancer.
Purpose of the Study:
- To investigate the function of ILC2s in pancreatic ductal adenocarcinoma (PDAC) immunity.
- To determine if ILC2s can be therapeutically targeted to enhance anti-PD-1 immunotherapy.
- To explore the presence and role of ILC2s in human PDAC.
Main Methods:
- Analysis of ILC2 infiltration and activation in mouse models of PDAC.
- Investigation of the effects of Interleukin-33 (IL33) on tumor-infiltrating ILC2s (TILC2s) and CD8+ T cells.
- Assessment of PD-1 expression on TILC2s and the impact of PD-1 blockade on anti-tumor immunity.
- Examination of PD-1+ TILC2s and T cells in human PDAC samples.
Main Results:
- ILC2s infiltrate PDAC and activate tissue-specific anti-tumor immunity.
- IL33 activates TILC2s and CD8+ T cells in pancreatic tumors, restricting tumor growth.
- TILC2s express the inhibitory receptor PD-1, and PD-1 blockade expands TILC2s and enhances anti-tumor immunity.
- PD-1+ TILC2s and T cells are prevalent in human PDAC, suggesting shared therapeutic targets.
Conclusions:
- ILC2s act as anti-cancer immune cells in PDAC and are potential targets for immunotherapy.
- ILC2s function as tissue-specific enhancers of cancer immunity, amplifying anti-PD-1 therapy efficacy.
- Targeting both ILC2s and T cells may represent a broadly applicable immunotherapeutic strategy for various cancers.
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