TY - JOUR
T1 - A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours
AU - Cui, Chang
AU - Chakraborty, Kasturi
AU - Tang, Xu Anna
AU - Schoenfelt, Kelly Q.
AU - Hoffman, Alexandria
AU - Blank, Ariane
AU - McBeth, Blake
AU - Pulliam, Natalie
AU - Reardon, Catherine A.
AU - Kulkarni, Swati A.
AU - Vaisar, Tomas
AU - Ballabio, Andrea
AU - Krishnan, Yamuna
AU - Becker, Lev
N1 - Funding Information:
We thank N. Hansen, K. Bethke and S. Khan, as well as B. LaBomascus at Northwestern University for assistance with obtaining tumours from ER+ breast cancer patients. Tfebfl/ fl mice were a gift from A. Ballabio, Telethon Institute of Genetics and Medicine. pMel and TRP1 mice were a gift from M. Swartz, University of Chicago. E0771 cells were a gift from M. Rosner, University of Chicago. B16F10 cells were a gift from T. Gajewski, University of Chicago. B16.OVA cells were a gift from J. Hubbell, University of Chicago. This work was supported by the Women’s Board Faculty Research Startup Funds and Ben May Department Startup Funds (L.B.), the University of Chicago Women’s Board (Y.K.) and the Ono Pharma Breakthrough Science Award (Y.K.). C.C. was supported by a Bernice Goldblatt Scholarship. K.C. was supported by a Schmidt Science Fellowship, in partnership with the Rhodes Trust. B.M. was supported by the National Cancer Institute (R25CA221767).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85118885342&partnerID=8YFLogxK
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U2 - 10.1038/s41565-021-00988-z
DO - 10.1038/s41565-021-00988-z
M3 - Article
C2 - 34764452
AN - SCOPUS:85118885342
SN - 1748-3387
VL - 16
SP - 1394
EP - 1402
JO - Nature Nanotechnology
JF - Nature Nanotechnology
IS - 12
ER -
