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A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours.
Cui, Chang; Chakraborty, Kasturi; Tang, Xu Anna; Schoenfelt, Kelly Q; Hoffman, Alexandria; Blank, Ariane; McBeth, Blake; Pulliam, Natalie; Reardon, Catherine A; Kulkarni, Swati A; Vaisar, Tomas; Ballabio, Andrea; Krishnan, Yamuna; Becker, Lev.
Afiliación
  • Cui C; Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.
  • Chakraborty K; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • Tang XA; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • Schoenfelt KQ; Department of Chemistry, The University of Chicago, Chicago, IL, USA.
  • Hoffman A; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • Blank A; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • McBeth B; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • Pulliam N; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • Reardon CA; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • Kulkarni SA; Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • Vaisar T; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • Ballabio A; Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • Krishnan Y; UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
  • Becker L; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Nat Nanotechnol ; 16(12): 1394-1402, 2021 12.
Article en En | MEDLINE | ID: mdl-34764452
Activating CD8+ T cells by antigen cross-presentation is remarkably effective at eliminating tumours. Although this function is traditionally attributed to dendritic cells, tumour-associated macrophages (TAMs) can also cross-present antigens. TAMs are the most abundant tumour-infiltrating leukocyte. Yet, TAMs have not been leveraged to activate CD8+ T cells because mechanisms that modulate their ability to cross-present antigens are incompletely understood. Here we show that TAMs harbour hyperactive cysteine protease activity in their lysosomes, which impedes antigen cross-presentation, thereby preventing CD8+ T cell activation. We developed a DNA nanodevice (E64-DNA) that targets the lysosomes of TAMs in mice. E64-DNA inhibits the population of cysteine proteases that is present specifically inside the lysosomes of TAMs, improves their ability to cross-present antigens and attenuates tumour growth via CD8+ T cells. When combined with cyclophosphamide, E64-DNA showed sustained tumour regression in a triple-negative-breast-cancer model. Our studies demonstrate that DNA nanodevices can be targeted with organelle-level precision to reprogram macrophages and achieve immunomodulation in vivo.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN / Nanopartículas / Macrófagos Asociados a Tumores / Lisosomas / Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Nat Nanotechnol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN / Nanopartículas / Macrófagos Asociados a Tumores / Lisosomas / Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Nat Nanotechnol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido