Tumor supportive M2-type macrophages generally prevail over their tumoricidal M1 counterparts in the tumor environment. It follows that efforts have been undertaken to either deplete M2-like cells or convert the macrophage phenotype into M1-like cells. M1- and M2-like polarization states differ in cell morphology and this divergence can be leveraged to individuate drugs that efficiently re-educate M2-like macrophages into M1-like cells.
A recent study reported that out of 38 tested drugs, agonists of the pattern recognition receptors toll-like receptor 7 and 8 (TLR7/8) exhibited the largest M1 polarization effects on murine M2-like cells. Resiquimod (R848), a dual TLR7/8 agonist, yielded M1 enrichments as pronounced as standard M1 induction by LPS and IFN-γ.
Macrophage avid β–Cyclodextrin nanoparticles (CDNP) were used by the authors to deliver R848 to TAMs (tumor associated macrophages) in an orthotopic lung adenocarcinoma model. R848 and the CDNP carrier co-localized at the subcellular level within TAMs. The CDNP-R848 formulation not only increased the local R848 concentration but also enhanced TAM re-education in vitro, as evidenced by the increased levels of M1-like transcripts in murine and human M2 macrophages.
Finally, an IL12-eYFP reporter mouse was used to monitor M1 induction by R848 in vivo. In contrast with naked R848, CDNP-R848 elicited a robust IL12 response, led to regression of mouse colorectal tumors, and generated long-term antitumor memory that resisted re-challenge.
The article, titled “TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy,” was published in Nature Biomedical Engineering.