A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours

Chang Cui; Kasturi Chakraborty; Xu Anna Tang; Kelly Q. Schoenfelt; Alexandria Hoffman; Ariane Blank; Blake McBeth; Natalie Pulliam; Catherine A. Reardon; Swati A. Kulkarni; Tomas Vaisar; Andrea Ballabio; Yamuna Krishnan; Lev Becker

doi:10.1038/s41565-021-00988-z

A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours

Chang Cui, Kasturi Chakraborty, Xu Anna Tang, Kelly Q. Schoenfelt, Alexandria Hoffman, Ariane Blank, Blake McBeth, Natalie Pulliam, Catherine A. Reardon, Swati A. Kulkarni, Tomas Vaisar, Andrea Ballabio, Yamuna Krishnan^*, Lev Becker^*

^*Corresponding author for this work

Surgery, Breast Surgery Division

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1394-1402
Number of pages	9
Journal	Nature nanotechnology
Volume	16
Issue number	12
DOIs	https://doi.org/10.1038/s41565-021-00988-z
State	Published - Dec 2021

Funding

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).

ASJC Scopus subject areas

Condensed Matter Physics
Bioengineering
Atomic and Molecular Physics, and Optics
General Materials Science
Electrical and Electronic Engineering
Biomedical Engineering

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41565-021-00988-z

Cite this

Cui, C., Chakraborty, K., Tang, X. A., Schoenfelt, K. Q., Hoffman, A., Blank, A., McBeth, B., Pulliam, N., Reardon, C. A., Kulkarni, S. A., Vaisar, T., Ballabio, A., Krishnan, Y., & Becker, L. (2021). A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours. Nature nanotechnology, 16(12), 1394-1402. https://doi.org/10.1038/s41565-021-00988-z

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abstract = "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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A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours

Abstract

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UN SDGs

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