TY - JOUR
T1 - Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma
AU - Jacquelot, Nicolas
AU - Seillet, Cyril
AU - Wang, Minyu
AU - Pizzolla, Angela
AU - Liao, Yang
AU - Hediyeh-zadeh, Soroor
AU - Grisaru-Tal, Sharon
AU - Louis, Cynthia
AU - Huang, Qiutong
AU - Schreuder, Jaring
AU - Souza-Fonseca-Guimaraes, Fernando
AU - de Graaf, Carolyn A.
AU - Thia, Kevin
AU - Macdonald, Sean
AU - Camilleri, Mary
AU - Luong, Kylie
AU - Zhang, Shengbo
AU - Chopin, Michael
AU - Molden-Hauer, Tristan
AU - Nutt, Stephen L.
AU - Umansky, Viktor
AU - Ciric, Bogoljub
AU - Groom, Joanna R.
AU - Foster, Paul S.
AU - Hansbro, Philip M.
AU - McKenzie, Andrew N.J.
AU - Gray, Daniel H.D.
AU - Behren, Andreas
AU - Cebon, Jonathan
AU - Vivier, Eric
AU - Wicks, Ian P.
AU - Trapani, Joseph A.
AU - Munitz, Ariel
AU - Davis, Melissa J.
AU - Shi, Wei
AU - Neeson, Paul J.
AU - Belz, Gabrielle T.
N1 - Funding Information:
E.V. is an employee of Innate Pharma. F.S.-F.-G. is a consultant and has a funded research agreement with Biotheus. P.N. has received research funding from Bristol Myers Squibb, Roche Genentech, Merck Sharp & Dohme, CRISPR Therapeutics, Allergan and Compugen. All other authors declare no competing interests.
Funding Information:
We thank J. Janssen, S. Cree, S. Shaw, E. Mettes, J. Leahy, F. Almeida, E. Pan, A. Johnston, D. Tantalo, members of the Belz, Neeson and Nutt laboratories, and members of the Flow Cytometry, Histology and Bioservices facilities at the Walter and Eliza Hall Institute of Medical Research for technical assistance and for helpful discussions. We express our gratitude to J. Cockwill, our long-term consumer representative, for fruitful discussions and significant consumer input. We are grateful to S. Wilcox and the Genomics platform for their technical help with scRNA-seq. The results published here are in part based upon data generated by the TCGA Research Network (https://www.cancer.gov/ tcga/). This work was supported by grants and fellowships from the National Health and Medical Research Council (NHMRC) of Australia (1165443, 1122277, 1054925 and 1135898 to G.T.B.; 1165443 and 1123000 to C.S.; 1175134 to P.M.H.; 1113577 and 1154325 to I.W.; 1158024 to D.H.D.G.; 1140406 to F.S.-F.-G.; 1155342 to S.L.N.; and 1196235 to M. Chopin), Reid Charitable Trusts (I.W.), a grant to The University of Queensland Chair of Immunology (Diamantina Institute, to G.T.B.), Cancer Council NSW (RG21-05 to G.T.B. and N.J.), Cure Cancer Australia and Cancer Australia through the Cancer Australia Priority-driven Cancer Research Scheme (1163990 to N.J., 1158085 to F.S-F.-G.), a fellowship from the Foundation ARC pour la recherche sur le cancer (to N.J.), Centenary Fellowships of the Walter and Eliza Hall Institute (sponsored by CSL, to J.G. and W.S.), a fellowship from the Victorian Government Department of Health and Human Services acting through the Victorian Cancer Agency (to A.B.), and the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation, 259332240/RTG 2099 to V.U.) and scholarships of the Australian Government Research Training Program (to Q.H.) and Melbourne Research Scholarship (to S.Z.). A.N.J.M. was supported by the UK Medical Research Council (U105178805). A.M. is supported by the US-Israel Binational Science Foundation (grant no. 2015163), the Israel Science Foundation (grant nos. 886/15 and 542/20), the Israel Cancer Research Fund, the Richard Eimert Research Fund on Solid Tumors (TAU), the Israel Cancer Association Avraham Rotstein Donation, the Cancer Biology Research Center (TAU) and the Emerson Collective. This research was carried out in part at the Translational Research Institute, Australia. The Translational Research Institute is supported by a grant from the Australian Government. This work was supported through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS.
Publisher Copyright:
© 2021, Crown.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85107501086&partnerID=8YFLogxK
U2 - 10.1038/s41590-021-00943-z
DO - 10.1038/s41590-021-00943-z
M3 - Article
C2 - 34099918
AN - SCOPUS:85107501086
SN - 1529-2908
VL - 22
SP - 851
EP - 864
JO - Nature Immunology
JF - Nature Immunology
IS - 7
ER -
