Medical Biology - Research Publications

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Author: Belz, Gabrielle × Author: Chopin, Michael × Author: Nutt, Stephen × Start date: 2000 × Type: Journal Article ×

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    Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma
    Jacquelot, N ; Seillet, C ; Wang, M ; Pizzolla, A ; Liao, Y ; Hediyeh-zadeh, S ; Grisaru-Tal, S ; Louis, C ; Huang, Q ; Schreuder, J ; Souza-Fonseca-Guimaraes, F ; de Graaf, CA ; Thia, K ; Macdonald, S ; Camilleri, M ; Luong, K ; Zhang, S ; Chopin, M ; Molden-Hauer, T ; Nutt, SL ; Umansky, V ; Ciric, B ; Groom, JR ; Foster, PS ; Hansbro, PM ; McKenzie, ANJ ; Gray, DHD ; Behren, A ; Cebon, J ; Vivier, E ; Wicks, IP ; Trapani, JA ; Munitz, A ; Davis, MJ ; Shi, W ; Neeson, PJ ; Belz, GT (NATURE PORTFOLIO, 2021-07)
    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.
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    Langerhans cells are generated by two distinct PU.1-dependent transcriptional networks
    Chopin, M ; Seillet, C ; Chevrier, S ; Wu, L ; Wang, H ; Morse, HC ; Belz, GT ; Nutt, SL (ROCKEFELLER UNIV PRESS, 2013-12-16)
    Langerhans cells (LCs) are the unique dendritic cells found in the epidermis. While a great deal of attention has focused on defining the developmental origins of LCs, reports addressing the transcriptional network ruling their differentiation remain sparse. We addressed the function of a group of key DC transcription factors-PU.1, ID2, IRF4, and IRF8-in the establishment of the LC network. We show that although steady-state LC homeostasis depends on PU.1 and ID2, the latter is dispensable for bone marrow-derived LCs. PU.1 controls LC differentiation by regulating the expression of the critical TGF-β responsive transcription factor RUNX3. PU.1 directly binds to the Runx3 regulatory elements in a TGF-β-dependent manner, whereas ectopic expression of RUNX3 rescued LC differentiation in the absence of PU.1 and promoted LC differentiation from PU.1-sufficient progenitors. These findings highlight the dual molecular network underlying LC differentiation, and show the central role of PU.1 in these processes.