Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers

Abstract

Tumor-associated macrophages (TAMs) usually express an M2 phenotype, which enables them to perform immunosuppressive and tumor-promoting functions. Reprogramming these TAMs toward an M1 phenotype could thwart their pro-cancer activities and unleash anti-tumor immunity, but efforts to accomplish this are nonspecific and elicit systemic inflammation. Here we describe a targeted nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. We demonstrate in models of ovarian cancer, melanoma, and glioblastoma that infusions of nanoparticles formulated with mRNAs encoding interferon regulatory factor 5 in combination with its activating kinase IKKβ reverse the immunosuppressive, tumor-supporting state of TAMs and reprogram them to a phenotype that induces anti-tumor immunity and promotes tumor regression. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this immunotherapy could enable physicians to obviate suppressive tumors while avoiding systemic treatments that disrupt immune homeostasis.

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

“…Gene therapy is a unique strategy to polarize TAMs. Zhang et al ( 174 ) describe using in vitro -transcribed mRNA encoding IRF5 and its activating kinase IKKβ encapsulated in nanoparticles to reprogram TAMs in models of ovarian cancer, melanoma, and GBM. The nanoparticles were engineered with D-mannose on the surface to efficiently and specifically target the mannose receptor CD206 + on TAMs.…”

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

“…Ex vivo treated-TAMs expressed increased levels of cytokines IL-12, IFN-γ, and TNF-α, while IL-6 was decreased. The same treatment was also effective in a murine model of glioma and lung metastasis [132].…”

Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

“…In particular, tumor-associated macrophages (TAMs) are one of the primary biological barriers in cancer tissue invariably encountered by NCs, so that scientists tried to exploit this "disadvantage" using TAMs as a reservoir of nanovehicles, to increase the site-specific drug release [13,77]. Another interesting progress is the design of NCs that can avoid phagocytosis through the modification of their surfaces (e.g., with CD47) [78] or that can modulate the polarization and activity of macrophages [79,80]. In addition, studies about the numerous molecular targets found to develop specific active targeted NCs brought huge knowledge.…”