Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs

Abstract

Local mRNA therapy encoding inflammatory cytokines and T cell costimulator OX40L mediates persistent anticancer immunity across tumor models. Sending tumors a message T cells need to overcome an immunosuppressive environment for successful cancer immunotherapy. Hewitt et al. leveraged a platform for mRNA delivery to devise a combination of factors that would ramp up antitumor immunity. They found that intratumoral injection of mRNAs encoding OX40L, IL-36γ, and IL-23 led to tumor regression in several cancer models. The triplet therapy also rendered normally resistant tumors susceptible to checkpoint blockade. The specific immune components responsible for protection were also dissected, and they showed that this local therapy led to systemic immunity. This mRNA treatment could one day be translated for patient benefit. Many solid cancers contain dysfunctional immune microenvironments. Immune system modulators that initiate responses to foreign pathogens could be promising candidates for reigniting productive responses toward tumors. Interleukin-1 (IL-1) and IL-12 cytokine family members cooperate at barrier tissues after microbial invasion, in human inflammatory diseases, and in antitumoral immunity. IL-36γ, in classic alarmin fashion, acts in damaged tissues, whereas IL-23 centrally coordinates immune responses to danger signals. In this study, direct intratumoral delivery of messenger RNAs (mRNAs) encoding these cytokines produced robust anticancer responses in a broad range of tumor microenvironments. The addition of mRNA encoding the T cell costimulator OX40L increased complete response rates in treated and untreated distal tumors compared to the cytokine mRNAs alone. Mice exhibiting complete responses were subsequently protected from tumor rechallenge. Treatments with these mRNA mixtures induced downstream cytokine and chemokine expression, and also activated multiple dendritic cell (DC) and T cell types. Consistent with this, efficacy was dependent on Batf3-dependent cross-presenting DCs and cytotoxic CD8+ T cells. IL-23/IL-36γ/OX40L triplet mRNA mixture triggered substantial immune cell recruitment into tumors, enabling effective tumor destruction irrespective of previous tumoral immune infiltrates. Last, combining triplet mRNA with checkpoint blockade led to efficacy in models otherwise resistant to systemic immune checkpoint inhibition. Human cell studies showed similar cytokine responses to the individual components of this mRNA mixture, suggesting translatability of immunomodulatory activity to human patients.