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.
Subject(s)
Antibodies/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Immune Checkpoint Inhibitors/pharmacology , Interleukin-33/pharmacology , Lymphocytes/drug effects , Melanoma, Experimental/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Skin Neoplasms/drug therapy , Animals , Cell Line, Tumor , Chemotaxis, Leukocyte/drug effects , Cytotoxicity, Immunologic/drug effects , Eosinophils/drug effects , Eosinophils/immunology , Eosinophils/metabolism , Female , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Lymphocytes/immunology , Lymphocytes/metabolism , Male , Melanoma, Experimental/genetics , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/immunology , Skin Neoplasms/metabolismABSTRACT
Dendritic cells (DCs) have critical roles in the induction of the adaptive immune response. The transcription factors Id2, Batf3 and Irf-8 are required for many aspects of murine DC differentiation including development of CD8α(+) and CD103(+) DCs. How they regulate DC subset specification is not completely understood. Using an Id2-GFP reporter system, we show that Id2 is broadly expressed in all cDC subsets with the highest expression in CD103(+) and CD8α(+) lineages. Notably, CD103(+) DCs were the only DC able to constitutively cross-present cell-associated antigens in vitro. Irf-8 deficiency affected loss of development of virtually all conventional DCs (cDCs) while Batf3 deficiency resulted in the development of Sirp-α(-) DCs that had impaired survival. Exposure to GM-CSF during differentiation induced expression of CD103 in Id2-GFP(+) DCs. It did not restore cross-presenting capacity to Batf3(-/-) or CD103(-)Sirp-α(-)DCs in vitro. Thus, Irf-8 and Batf3 regulate distinct stages in DC differentiation during the development of cDCs. Genetic mapping DC subset differentiation using Id2-GFP may have broad implications in understanding the interplay of DC subsets during protective and pathological immune responses.
Subject(s)
Antigens, CD/metabolism , CD8 Antigens/metabolism , Cell Lineage/genetics , Dendritic Cells/physiology , Inhibitor of Differentiation Protein 2/genetics , Integrin alpha Chains/metabolism , Animals , Cell Differentiation/genetics , Cell Differentiation/physiology , Cells, Cultured , Dendritic Cells/metabolism , Gene Expression/physiology , Genes, cdc/physiology , Inhibitor of Differentiation Protein 2/physiology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Models, BiologicalABSTRACT
Adult-onset Still's disease (AOSD) is a rare autoinflammatory condition diagnosed by Yamaguchi criteria. We report an atypical presentation of a 73-year-old man, who was admitted with fever, sore throat and pleurisy that were unresponsive to three courses of antibiotics. Fever persisted in a quotidian pattern and the typical salmon-coloured rash consistent with AOSD appeared at 4 weeks from symptoms onset. These features in addition to neutrophilia and hyperferritinaemia in the absence of concurrent infectious and neoplastic causes satisfied Yamaguchi criteria for a diagnosis of AOSD. Epstein-Barr antigen was initially detected at moderate titre levels, but was undetectable after 1 week. Complete resolution of symptoms was reported on initiation of steroid treatment. A relationship between disease onset and viral syndromes has been documented to occur and few similar cases preceded by Epstein-Barr virus detection have been reported.