Landscape and functional impact of missense mutations of immune response genes in human cancer

Abstract Tumor-intrinsic defects in immune recognition and interferon-gamma (IFNγ) signaling pathways facilitate immune evasion and limit the efficacy of immune checkpoint blockade (ICB). Here, we delineate the mutational landscape and functional consequences of amino acid substitutions in key immune-related genes, B2M, CALR, IFNGR1, IFNGR2, JAK1, and JAK2, across more than 12 000 primary tumors and cancer cell lines. Genomic alterations affecting the coding regions of at least one of these genes were identified in approximately 11% of cancers, with missense variants accounting for 55% of these events. B2M exhibited the highest mutation frequency per base pair, the mutations predominantly involving truncating variants. A curated set of 215 missense mutations in B2M, IFNGR1, IFNGR2, and JAK2 was interrogated using SIFT, PolyPhen-2, and AlphaMissense, yielding predicted pathogenicity rates of 52%, 35%, and 27%, respectively. Functional assays revealed JAK2 and IFNGR1 variants that impaired IFNγ-mediated transcriptional activation and growth suppression, and B2M variants that disrupted HLA class I complex formation. Notably, AlphaMissense predictions showed the highest concordance with experimental data. These findings provide a detailed mutational map of antigen presentation and IFNγ-response components in cancer, offering a resource of specific mutations in immune pathways that compromise tumor immunogenicity and may influence the response to ICB.