Harnessing RIG-I in the tumor microenvironment for therapeutic breast cancer treatment

Abstract

RIG-I is a cytoplasmic RNA helicase expressed in most cells of the body, functioning to sense viral oligonucleotide motifs then activate innate immune responses to combat viral infection. RIG-I expression and activity is retained in most cancer cells and cells of the tumor microenvironment (TME). These observations support a growing research interest in potential use of synthetic RIG-I agonists in cancer therapy. Using an engineered RIG-I agonist, SLR20, we tested the applicability of therapeutic RIG-I activation in breast cancer. SLR20 treatment triggered the extrinsic apoptosis and pyroptosis cell death pathways in breast cancer cells. SLR20 treatment, in vivo, increased tumor infiltrating lymphocytes and decreased mammary tumor growth and metastasis. T-cell activation and tumor cell killing was increased upon co-culture of T-cells with SLR20-treated breast cancer cells, and dual immunization of wild-type mice with SLR20 and 4T1 cancer cell lysates reduced future tumor growth. Overall, these findings demonstrate hat RIG-I agonist have the capacity to induce tumor cell killing and modulate the tumor microenvironment in vivo. These reports indicate that therapeutic RIG-I signaling operates at the interface of innate and adaptive immunity within breast tumors to redirect T-cell responses in the TME.