Survivin mRNA-lipid nanoparticles promote activation of CD8+Granzyme B+ T cells and effector memory formation for effective oral cancer immunotherapy.

Abstract

Effective cancer immunotherapy requires an understanding of the tumor microenvironment (TME) to overcome immune suppression and provide a durable anti-tumor response. Here, we present preclinical evaluation of survivin antigen-encoded mRNA lipid nanoparticles (mRNA-LNPs) in a murine oral cancer model. In vivo anti-tumor efficacy studies in early-stage tumors (induced by MOC1 cells, tumor volume ∼100 mm3) showed complete tumor elimination within 7-10 days after survivin mRNA-LNPs administration. The mechanistic studies performed to analyze immune cell (including dendritic cells and T cells) activation using flow cytometry and complementary cytokine profiling by ELISA revealed immune reprogramming. Survivin mRNA-LNP administration showed a broad, multi-compartmental T-cell immune response compared with control group. The treatment group showed significantly greater CD4+ and CD8+ T cell expansion in lymph nodes by day 3 (p<0.0001) and robust infiltration into the TME by day 14 (p<0.001) compared with control group. The survivin mRNA-LNPs promoted T cell activation (CD69+, CD28+) and increased cytotoxic CD8+Granzyme B+ T cells in the TME (p<0.001). The survivin mRNA-LNPs group showed controlled Treg levels in the TME providing a favorable effector to Treg ratio critical for superior anti-tumor efficacy. Furthermore, tumor rechallenge study showed formation of immunological memory against oral cancer cells. In conclusion, the present study provides a mechanistic understanding of survivin mRNA-LNP-mediated immune modulation in oral cancer immunotherapy.