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Background: In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mechanisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I molecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHC I complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms., Methods: Bioinformatics analyses of IRF2 and IRF2-dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein-DNA-binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo., Results: Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2-regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlations and the consequences of IRF2 loss, we gene-edited IRF2 in a patient-derived melanoma and a mouse melanoma. The IRF2 gene-edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell killing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2-deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI., Conclusions: Our study shows that a subset of cases within most types of cancers downregulates IRF2 and that this can allow cancers to escape immune control. This can cause resistance to checkpoint blockade immunotherapy and is reversible with currently available biologics., (© 2024. The Author(s).)

There is an increased rate of reported autoantibody production in patients with atopic and nonatopic asthma. The possibility of generating autoantibodies after the induction of immunotherapy can be explained by several mechanisms. One of these is immune deviation from TH2 to TH1 response by the effect of immunotherapy in favor of unregulated response to self-antigens. The other theory is a possible antigenic mimicry enabling autoantibody formation in these patients, Sixty-three atopic asthmatic children were included in the study. The patients were divided into three groups: Group I: patients with atopic bronchial asthma without immunotherapy: Group II: patients receiving immunotherapy for a maximum of 3 years; Group III: patients receiving immunotherapy for 4-5 years. The autoantibodies examined in the study population were anti-nuclear antibody, anti-double stranded DNA, rheumatoid factor, liver-kidney microsomal antibody, anti-mitochondrial antibody, anti-thyroglobulin and anti-microsomal antibody, anti-Smith antibody and lupus anticoagulant. An overall incidence of 17.5% autoantibody positivity was observed in patients, with no statistical significance between the treatment groups. IgG levels were significantly elevated in Group III when compared with Group I. Based on these findings it is suggested, in accordance with other studies, that long-term immunotherapy in the pediatric age group does not cause a significant autoantibody formation other than the overall increased incidence that occurs in asthmatic patients.