T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles
Verena Turco, Kira Pfleiderer, Jessica Hunger, Natalie K. Horvat, Kianush Karimian‐Jazi, Katharina Schregel, Manuel Fischer, Gianluca Brugnara, Kristine Jähne, Volker Sturm, Yannik Streibel, Duy Nguyen, Sandro Altamura, Dennis A. Agardy, Shreya S. Soni, Abdulrahman Alsasa, Theresa Bunse, Matthias Schlesner, Martina U. Muckenthaler, Ralph Weissleder, Wolfgang Wick, Sabine Heiland, Philipp Kickingereder, Martin Bendszus, Christopher B. Rodell, Michael O. Breckwoldt, Michael Platten
Abstract
Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically "cold" tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.