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

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), 2020-03, Vol.579 (7797), p.130-135 [Periódico revisado por pares]

England: Nature Publishing Group

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ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity
Autor: 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
Assuntos: 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 ; 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 ; 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 ; T-Lymphocytes - immunology ; Tissues ; Transcription ; Tumor-infiltrating lymphocytes ; Tumors
É parte de: Nature (London), 2020-03, Vol.579 (7797), p.130-135
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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
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

England: Nature Publishing Group

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