p300/CBP mediated activation of MHCI machinery and IFNg receptor loci controls chemoimmunotherapy
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. Overall design: To investigate Oxali's effects on CD8+ T cells, we sorted tumor-infiltrating CD8+ T cells (TI-CD8+) from subcutaneous (s.c.) Myc-CaP tumors, which were treated weekly with either Oxali, aPD-L1, both (combo) or left untreated (Ctrl) and performed scRNA-seq. Droplet-based 3' end massively parallel single-cell RNA sequencing was performed by encapsulating sorted live TI-CD8+ into droplets and libraries prepared using Chromium Single Cell 30 Reagent Kits V3 according to manufacturer's protocol (10x Genomics).