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P300/CBP mediated activation of MHCI machinery and IFNg receptor loci controls chemoimmunotherapy

ABSTRACT: Certain chemotherapeutic drugs potentiate responses to immune checkpoint inhibitors (ICI), including PD-(L)1 antibodies, but the mechanisms underlying this synergism are poorly understood. Many cancers evade immune rejection by suppressing MHC-I antigen processing and presentation (AgPP). We show that two classes of DNA damaging drugs, platinoids (e.g. oxaliplatin) and topoisomerase inhibitors (e.g. mitoxanthrone), induce NF-kB activation, nuclear translocation of the histone and lysine acetyl transferases p300/CBP, interferon (IFN) regulatory factors and IFNg receptor 2 (IFNgR2). This results in transcriptional activation of loci coding for the MHC-I transactivator NLRC5 and components of the MHC-I AgPP machinery. Accordingly, p300 inactivation prevents drug-induced upregulation of MHC-I antigen presentation leading to impaired recognition of cancer cells by effector CD8+ T cells, whose tumor rejecting activity is IFNgR2-dependent. Correspondingly, EP300 loss in human cancers correlates with reduced expression of MHC-I related genes and/or changes in neoantigen amount and expression, suggesting that p300 is an immune-directed oncosuppressor.

ORGANISM(S): Mus musculus

PROVIDER: GSE151611 | GEO | 2021/02/01

REPOSITORIES: GEO

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