Pharmacological Modulation of B16-F10 Murine Melanoma-Induced TAMs Functional Phenotype via Lipoprotein-Based Nanoparticles

Akpedje S. Dossou, Nirupama Sabnis, Andras Lacko, Rafal Fudala

Research output: Contribution to journalArticlepeer-review

Abstract

Tumor-associated macrophages (TAMs) are one of the most abundant immune cells in the tumor microenvironment (TME). Their immunosuppressive phenotype (M2) promotes tumor progression. The re-education of TAMs in the TME to a pro-immune phenotype (M1) is considered to enhance the effectiveness of the anti-tumor immune response and leads to tumor regression. An effective therapeutic approach utilizing macrophage re-polarization will likely require the selective delivery of agents to the TME to execute the M2-to-M1 phenotype transformation. This strategy is known to avoid adverse immune-related events through the utilization of nanocarriers that can effectively penetrate the TME and interact with TAMs. As a drug delivery platform, reconstituted high-density lipoprotein nanoparticles (rHDL NPs) have attracted increased interest in cancer therapeutics, owing to their biocompatibility and their capacity to transport lipophilic drugs toward their accumulation in the tumor. We and others have shown that the scavenger receptor class B type 1 (SR-B1), at the surface of target cells, mediates the intracellular (non-endocytic) delivery of rHDL NPs' payload. The novel lipophilic agonist of the STimulator of INterferon Genes (STING), MSA-2, has been used successfully to mediate the M2-to-M1 reversal in murine models of cancer. In this study, we aim to deliver MSA-2 to TAMs using mannose-decorated rHDL NPs to induce a conversion to an M1 phenotype. Because TAMs highly express the mannose receptor CD206 that facilitates the interaction of mannose with TAMs, inducing an M1 phenotype, we anticipate a successful outcome based on this strategy. We prepared and validated the retention of the PEGylated mannose moiety on the rHDL NPs. Fluorescence anisotropy and absorbance studies showed that rHDL NPs successfully encapsulated MSA-2. IL-4-induced M2 macrophages and B16-F10 murine melanoma conditioned media-induced TAMs showed a higher SR-B1 expression compared to M1 macrophages. The lower uptake of the surrogate dye payload by M1 macrophages (compared to M2 macrophages and TAMs) from the mannose-decorated rHDL NPs, corroborates the importance of the SR-B1 receptor in rHDL payload delivery. The above findings have significant therapeutic implications for the strategy of utilizing mannose-decorated rHDL-NPs to selectively target TAMs in the tumor microenvironment. In addition, this formulation of MSA-2 with the mannose-decorated rHDL NPs can be applied in a synergistic combination with mainstream immunotherapies to improve treatment outcomes for cancer patients, diagnosed with solid tumors.

Original languageEnglish
JournalFASEB Journal
Volume36
DOIs
StatePublished - 1 May 2022

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