Alphavirus replicon particle expressing IL-12 reprograms tumor-associated macrophages and neutrophils and induces anti-tumor immunity

Abstract

Cancers evade anti-tumor immunity by the infiltration of immunosuppressive myeloid cells such as macrophages and neutrophils into the tumor microenvironment (TME). The limited efficacy of current immunotherapy is attributed to the presence of these immunosuppressive cells. Here, we describe a novel immunotherapy approach, using a single-cycle alphavirus replicon particle (VRP) that carries a self-amplifying RNA encoding interleukin-12 (IL-12). Leveraging the natural tropism of alphavirus to myeloid cells, single cell transcriptomic analyses of mouse tumor tissues demonstrated that intratumoral (i.t.) injection of the vector effectively reprogrammed tumor-associated macrophages and neutrophils toward a pro-inflammatory, anti-tumor phenotype via interferon signaling, further enhanced by IL-12 expression. The treatment also induced cytotoxic NK and T cell responses, resulting in a significant reduction of tumor growth and effectively preventing nodal and distant metastases in solid tumor mouse models. By targeting tumor-supporting myeloid cells to transform the TME into an immune-active state, our myeloid modulation approach has the potential to enhance the efficacy of current immunotherapies.