Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation

Abstract

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I–dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I–expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had “epigenetically down-regulated,” but had not permanently lost MHC-I AgPP activity.

Tyrosine Kinase Inhibitors Stimulate HLA Class I Expression by Augmenting the IFNγ/STAT1 Signaling in Hepatocellular Carcinoma Cells

“…Gene expression correlations were assessed according to the Spearman coefficient. Genes associated with T cell inflammation were selected in accordance with a previous report ( 27 ).…”

Regulation of antitumor immunity by inflammation-induced epigenetic alterations

“…Both loss-and gain-offunction mutations in the human EP300 locus were described to enhance tumor progression, suggesting context-dependent tumor-suppressive or oncogenic functions [94,95]. EP300 downregulation in human cancer was associated with reduced MHC-I AgPPM expression and changes in neoantigen amounts and presentation [90]. Collectively, these studies confirm that epigenetic processes play pivotal roles in the immune evasion capabilities of cancer cells.…”

“…For instance, DNA methylation and certain histone modifications contribute to silencing of various genes involved in antigen processing and presentation, as well as tumorassociated antigen genes, MHC class I and II genes and Chromatin remodeling also regulates the response to cytotoxic attack in cancer cells. Epigenetic modifying agents (EMAs) can enhance multiple aspects of the antitumor immune response costimulatory molecule genes [90,91]. In this regard, treatment of cancer cells with epigenetic therapies such as HDACis or HAT activators leads to upregulation of NK cell ligands [92] and AgPPM components, including tumor-associated antigens, cancer testis antigens, immunoproteasome subunits, peptide transporters, NLRC5, and MHC class I and II molecules [90].…”

“…Epigenetic modifying agents (EMAs) can enhance multiple aspects of the antitumor immune response costimulatory molecule genes [90,91]. In this regard, treatment of cancer cells with epigenetic therapies such as HDACis or HAT activators leads to upregulation of NK cell ligands [92] and AgPPM components, including tumor-associated antigens, cancer testis antigens, immunoproteasome subunits, peptide transporters, NLRC5, and MHC class I and II molecules [90]. For instance, colorectal cancer cells deficient in DNMTs show decreased methylation and increased expression of MHC class I genes and NK cell ligands [93].…”

Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

“…Remarkably, alongside the DIX effect, chemotherapy is also able to intensify tumor cell immunogenicity by stimulating the expression of MHC-I molecules [ 267 ]. Moreover, cytotoxic agents could provide additional anti-cancer mechanisms, including the activation of NK cells by stimulating the specific NKG2D ligand and the induction of DC differentiation as well as the improvement of T-cell functionality.…”