Depletion of tumor associated macrophages enhances local and systemic platelet-mediated anti-PD-1 delivery for post-surgery tumor recurrence treatment

Zhaoting Li, Yingyue Ding, Jun Liu, Jianxin Wang, Fanyi Mo, Yixin Wang, Ting-Jing Chen-Mayfield, Paul M. Sondel, Seungpyo Hong and Quanyin Hu ()
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Zhaoting Li: University of Wisconsin-Madison
Yingyue Ding: University of Wisconsin-Madison
Jun Liu: University of Wisconsin-Madison
Jianxin Wang: University of Wisconsin-Madison
Fanyi Mo: University of Wisconsin-Madison
Yixin Wang: University of Wisconsin-Madison
Ting-Jing Chen-Mayfield: University of Wisconsin-Madison
Paul M. Sondel: University of Wisconsin-Madison
Seungpyo Hong: University of Wisconsin-Madison
Quanyin Hu: University of Wisconsin-Madison

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir.

Date: 2022
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DOI: 10.1038/s41467-022-29388-0

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