Engineered macrophages accumulate in solid tumors and locally deliver immune-activating proteins to inhibit tumor progression.

BACKGROUND: Currently, immune checkpoint inhibitors (ICIs) and other immune-activating strategies represent the main approach to cancer treatment; however, immune resistance in many solid tumors limits the immune therapy response and can cause strong toxic side effects. In solid tumors, the development of effective anti-tumor immune responses is hindered by limited immune cell infiltration and an immunosuppressive tumor microenvironment (TME). To overcome current immunotherapy challenges, we proposed a novel approach providing local and stable treatment levels to activate or revitalize anti-tumor immunity, to achieve the effect of TME infiltration and sustained presence in solid tumors. METHODS: Using genetic engineering methods to synergistically activate immunity in the TME, we programmed macrophages to express therapeutic payloads, including interleukin (IL)-12 and the signal regulatory protein alpha-Fragment crystallizable fusion protein (SIRPα-Fc), a CD47 ICI. Co-culture studies were performed to evaluate the effects of the genetically engineered macrophages (GEMs) on the T cells and GEMs themselves in vitro. We evaluated the tumor response, cellular response, and cytokine response. The GEMs were administered to a mouse model of tumor-cell transplantation, where they were retained and expressed as lentiviral payloads. RESULTS: The IL-12 secreted by the GEMs provided effector signals for T cells, thereby enhancing the tumor resident anti-tumor macrophages and CD8(+)T-cell populations. In addition, the secretion of SIRPα-Fc enhanced the phagocytic activity of the macrophages toward tumor cells and promoted their antigen presentation function. The combination therapy of dual proteins produced significant synergistic effects in solid tumor models and further enhanced memory immunity. The GEMs also improved the efficacy of ICIs in the ICI-resistant gene engineering tumor models and demonstrated significant anti-tumor efficacy in the metastasis models. CONCLUSIONS: Our study showed the potential clinical application of GEMs in the treatment of tumors.