2024-04-08 CANCER CELL 2024 42(卷), 4(期), (null页)
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 b2-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 mRNAencoded interleukin-2 (IL -2) restores an immune cell infiltrated, IFNg-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 IFNg-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.
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