An mRNA-encoded, long-lasting Interleukin-2 restores CD8⁺T cell neoantigen immunity in MHC class I-deficient cancers

Abstract

MHC class I antigen presentation deficiencies are considered to be the most prevalent cancer immune escape mechanism. Despite their increasing occurrence, the mechanistic implications, and potential strategies to address this challenge, remain poorly understood. Studying β2-microglobulin (B2M) deficient mouse tumor models, we found that MHC class I loss leads to a substantial decrease in immune stimulatory cytokines resulting in an immune desertification of the tumor microenvironment (TME) and broad therapeutic resistance, encompassing immuno-, chemo- and radiotherapy. We show that treatment with long-lasting mRNA-encoded interleukin-2 (IL2) restores tumor immune infiltration, and when combined with a tumor-targeting monoclonal antibody (mAb), can overcome therapeutic resistance. Surprisingly, we identified that effectiveness of this treatment is primarily driven by neoantigen-specific CD8+ T cells that recognize neo-antigens taken up and presented by macrophages in the TME. Our findings highlight the unexpected importance of restoring neoantigen-specific immune responses in the treatment of cancers with MHC class I deficiencies.