Although present in skin, innate lymphoid cells (ILCs) have not been fully explored as a therapeutic target in melanoma. Jacquelot et al. showed that high Group 2 ILC (ILC2) infiltration was associated with favorable outcomes in melanoma patients. In addition to IL-5 and -13, ILC2s produced high levels of GM-CSF in the TME, resulting in increased numbers of eosinophils with enhanced cytotoxicity. High levels of PD-1 expression on intratumoral ILC2s inhibited ILC2-driven antitumor efficacy, but could be overcome by treating in vivo with anti-PD-1, especially when combined with anti-CD33, a known ILC2 activator.
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. nicolas.jacquelot@uhnresearch.ca. Department of Medical Biology, University of Melbourn
Author Info: (1) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. nicolas.jacquelot@uhnresearch.ca. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. nicolas.jacquelot@uhnresearch.ca. Princess Margaret Cancer Centre, Toronto, Ontario, Canada. nicolas.jacquelot@uhnresearch.ca. (2) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. (5) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. (6) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (7) Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (8) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (9) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia. (10) The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia. (11) The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia. (12) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (15) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (16) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (17) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (18) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (19) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (20) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (21) Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. (22) Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA. (23) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (24) Priority Research Centres for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia. (25) Priority Research Centres for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia. Centre for Inflammation, Centenary Institute, Sydney, New South Wales, Australia. School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia. (26) Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. (27) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. (28) Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia. (29) Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia. Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, Victoria, Australia. (30) Innate Pharma Research Labs, Marseille, France. Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. Service d'Immunologie, Marseille Immunopole, Hpital de la Timone, Assistance Publique-Hpitaux de Marseille, Marseille, France. (31) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. Rheumatology Unit, Royal Melbourne Hospital, Melbourne, Australia. (32) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. (33) Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (34) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Department of Computing and Information Systems, University of Melbourne, Melbourne, Victoria, Australia. (35) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. Department of Computing and Information Systems, University of Melbourne, Melbourne, Victoria, Australia. (36) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. (37) The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. g.belz@uq.edu.au. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. g.belz@uq.edu.au. The University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia. g.belz@uq.edu.au.
