TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy

Abstract

Tumour-associated macrophages are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance to therapy. Yet, macrophages are highly plastic and can also acquire an anti-tumorigenic M1-like phenotype. Here, we show that R848, an agonist of the toll-like receptors TLR7 and TLR8 identified in a morphometric-based screen, is a potent driver of the M1 phenotype in vitro and that R848-loaded β-cyclodextrin nanoparticles (CDNP-R848) lead to efficient drug delivery to tumour-associated macrophages in vivo. As a monotherapy, the administration of CDNP-R848 in multiple tumour models in mice altered the functional orientation of the tumour immune microenvironment towards an M1 phenotype, leading to controlled tumour growth and protecting the animals against tumour rechallenge. When used in combination with the immune checkpoint inhibitor anti-PD-1, we observed improved immunotherapy response rates, including in a tumour model resistant to anti-PD-1 therapy alone. Our findings demonstrate the ability of rationally engineered drug–nanoparticle combinations to efficiently modulate tumour-associated macrophages for cancer immunotherapy.

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Fig. 1: Proposed strategy for high-content screening the therapeutic re-education macrophages.
Fig. 2: In vitro assessment of macrophage phenotype.
Fig. 3: Development and characterization of CDNPs.
Fig. 4: In vivo biodistribution and pharmacokinetics of CDNP.
Fig. 5: Uptake of CDNPs by TAMs.
Fig. 6: Intravital re-education of TAMs.
Fig. 7: Therapeutic efficacy.

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Acknowledgements

This work was supported in part by grants from the US National Institutes of Health (NIH T32CA079443; R01CA206890; U01CA206997; R01HL131495). We thank H. Im, A. Magnuson and M. Miller for assistance with some of the experiments and G. Wojtkiewicz and M. Prytyskach for technical help. Our special thanks go to C. Benoist and D. Mathis for critical review of the data, helpful suggestions and general discussions. The anti-PD1 antibody was a kind gift from G. J. Freeman.

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R.W. and C.B.R. conceived and designed the CDNP–drug conjugate. C.B.R., S.P.A., M.F.C., C.S.G., R.L., M.S.A. and R.H.K. performed the experiments and data analysis. C.B.R., S.P.A., M.J.P. and R.W. wrote the manuscript. All authors contributed feedback on the final manuscript.

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Correspondence to Ralph Weissleder.

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C.B.R. and R.W. are listed on a patent filed by Partners Healthcare. The remaining authors declare no competing interests.

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Rapid uptake of CDNPs by tumour-associated macrophages in vivo.

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Rodell, C.B., Arlauckas, S.P., Cuccarese, M.F. et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat Biomed Eng 2, 578–588 (2018). https://doi.org/10.1038/s41551-018-0236-8

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