Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma

• Published in: Nature immunology Vol. 22; no. 7; pp. 851 - 864
• Main Authors: Jacquelot, Nicolas, Seillet, Cyril, Wang, Minyu, Pizzolla, Angela, Liao, Yang, Hediyeh-zadeh, Soroor, Grisaru-Tal, Sharon, Louis, Cynthia, Huang, Qiutong, Schreuder, Jaring, Souza-Fonseca-Guimaraes, Fernando, de Graaf, Carolyn A., Thia, Kevin, Macdonald, Sean, Camilleri, Mary, Luong, Kylie, Zhang, Shengbo, Chopin, Michael, Molden-Hauer, Tristan, Nutt, Stephen L., Umansky, Viktor, Ciric, Bogoljub, Groom, Joanna R., Foster, Paul S., Hansbro, Philip M., McKenzie, Andrew N. J., Gray, Daniel H. D., Behren, Andreas, Cebon, Jonathan, Vivier, Eric, Wicks, Ian P., Trapani, Joseph A., Munitz, Ariel, Davis, Melissa J., Shi, Wei, Neeson, Paul J., Belz, Gabrielle T.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2021; Nature Publishing Group
• Subjects: 631/250/2504/2506; 631/67/580/1884; Animals; Antibodies - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antitumor activity; Apoptosis; Biomedical and Life Sciences; Biomedicine; Care and treatment; Cell activation; Cell death; Cell Line, Tumor; Cell receptors; Chemotaxis, Leukocyte - drug effects; Colonies; Colony-stimulating factor; Cytokines; Cytotoxicity, Immunologic - drug effects; Development and progression; Eosinophils - drug effects; Eosinophils - immunology; Eosinophils - metabolism; Female; Genetic aspects; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Granulocytes; Health aspects; Homeostasis; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune response; Immunity; Immunology; Immunotherapy; Infectious Diseases; Inflammation; Interleukin-33 - pharmacology; Leukocytes (eosinophilic); Life Sciences; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphoid cells; Male; Melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Metastases; Mice; Mice, Inbred C57BL; Mice, Knockout; PD-1 protein; Phenotype; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - immunology; Skin Neoplasms - metabolism; Tumor microenvironment; Australia
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-021-00943-z

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. Group 2 innate lymphoid cells (ILC2s) are generally considered to have pro-tumor functions. However, Belz and colleagues demonstrate that ILC2s have anti-melanoma effects due to their high production of the inflammatory cytokine granulocyte-macrophage colony-stimulating factor in the tumor microenvironment.