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Moral, John Alec; Leung, Joanne; Rojas, Luis A; Ruan, Jennifer; Zhao, Julia; Sethna, Zachary; Ramnarain, Anita; Gasmi, Billel; Gururajan, Murali; Redmond, David; Askan, Gokce; Bhanot, Umesh; Elyada, Ela; Park, Youngkyu; Tuveson, David A; Gönen, Mithat; Leach, Steven D; Wolchok, Jedd D; DeMatteo, Ronald P; Merghoub, Taha; Balachandran, Vinod P
Nature (London), 03/2020, Volume: 579, Issue: 7797Journal Article
Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues . Although ILC2s are found in cancers of these tissues , 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.
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