ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity

Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues 1 , 2 . Although ILC2s are found in cancers of these tissues 3 , their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to...

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Veröffentlicht in:	Nature (London) Jg. 579; H. 7797; S. 130 - 135
Hauptverfasser:	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.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 05.03.2020 Nature Publishing Group
Schlagworte:	13/1 13/106 13/31 13/51 38/39 38/91 631/250/2504 631/67/1504/1713 631/67/580 64/60 Analysis Animals Anticancer properties Antigen processing Antigens Apoptotic proteins Cancer Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - immunology Care and treatment CD45 antigen CD90 antigen Cell activation Cellular immunity Control Cytokines Dendritic Cells - immunology Euthanasia Female Gene sequencing Genotype & phenotype Humanities and Social Sciences Humans Immune system Immunity Immunity, Innate - immunology Immunotherapy Interleukin-33 - immunology Lymphatic system Lymphocyte Activation Lymphocytes Lymphocytes - immunology Lymphocytes T Major histocompatibility complex Male Mice Mice, Inbred C57BL multidisciplinary Organs Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - immunology Patient outcomes PD-1 protein Physiological aspects Priming Programmed Cell Death 1 Receptor - antagonists & inhibitors Ribonucleic acid RNA Science Science (multidisciplinary) T-Lymphocytes - immunology Transcription Tumor-infiltrating lymphocytes Tumors United States
ISSN:	0028-0836, 1476-4687, 1476-4687
Online-Zugang:	Volltext
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Zusammenfassung:	Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues 1 , 2 . Although ILC2s are found in cancers of these tissues 3 , 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. Tumour-infiltrating group 2 innate lymphoid cells prime CD8 + T cells and amplify the anti-tumour effects of PD-1 blockade in pancreatic ductal adenocarcinoma.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work. V.P.B. conceived the study. J.A.M, J.L., L.A.R., S.D.L., J.D.W., R.P.D., T.M., and V.P.B. designed all experiments. J.A.M, J.L., L.A.R., J.R., J.Z., A.R. and V.P.B., performed all the experiments. B.G. assisted with generation of bone marrow chimeras. J.L., Z.S., and D.R. analyzed the scRNA-seq results. G.A., and U.B. performed the pathologic analyses. E.E., Y.P., and D.A.T. generated and assisted in experiments on autochthonous KPC mice. M.G. provided technical assistance with PD-1 blocking antibody. M. Gonen provided statistical oversight. J.A.M, J.L., L.A.R., J.R., S.D.L., R.P.D., T.M., and V.P.B, analyzed all the data. All authors interpreted the data. J.A.M., and V.P.B. wrote the manuscript with input from all authors. Author Contributions
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-020-2015-4