Long-lasting mRNA-encoded interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers

Major histocompatibility complex (MHC) class I antigen presentation deficiency is a common cancer immune escape mechanism, but the mechanistic implications and potential strategies to address this challenge remain poorly understood. Studying β2-microglobulin (B2M) deficient mouse tumor models, we find that MHC class I loss leads to a substantial immune desertification of the tumor microenvironment (TME) and broad resistance to immune-, chemo-, and radiotherapy. We show that treatment with long-lasting mRNA-encoded interleukin-2 (IL-2) restores an immune cell infiltrated, IFNγ-promoted, highly proinflammatory TME signature, and when combined with a tumor-targeting monoclonal antibody (mAB), can overcome therapeutic resistance. Unexpectedly, the effectiveness of this treatment is driven by IFNγ-releasing CD8+ T cells that recognize neoantigens cross-presented by TME-resident activated macrophages. These macrophages acquire augmented antigen presentation proficiency and other M1-phenotype-associated features under IL-2 treatment. Our findings highlight the importance of restoring neoantigen-specific immune responses in the treatment of cancers with MHC class I deficiencies. [Display omitted] •MHC class I loss leads to immune desertification and resistance to therapy in tumors•Tumor-targeting antibody and IL-2 mRNA overcomes this therapeutic resistance•Therapeutic efficacy depends on M1-like macrophages, IFNγ, and CD8+ T cells•IFNγ-releasing CD8+ T cells recognize neoantigens cross-presented by macrophages MHC-I antigen presentation deficiency is a common cancer immune escape mechanism. Beck et al. show that combining tumor-targeting antibodies with IL-2 mRNA induces rejection of MHC class I-deficient tumors otherwise resistant to immune-, chemo-, and radiotherapy. Unexpectedly, efficacy is dependent on a crosstalk between CD8+ T cells and macrophages.