Antitumor Effects of Epidrug/IFNα Combination Driven by Modulated Gene Signatures in Both Colorectal Cancer and Dendritic Cells

Abstract

Colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations. IFN signaling defects play an important role in the carcinogenesis process, in which the inability of IFN transcription regulatory factors (IRF) to access regulatory sequences in IFN-stimulated genes (ISG) in tumors and in immune cells may be pivotal. We reported that low-dose combination of two FDA-approved epidrugs, azacytidine (A) and romidepsin (R), with IFNα2 (ARI) hampers the aggressiveness of both colorectal cancer metastatic and stem cells and triggers immunogenic cell death signals that stimulate dendritic cell (DC) function. Here, we investigated the molecular signals induced by ARI treatment and found that this drug combination increased the accessibility to regulatory sequences of ISGs and IRFs that were epigenetically silenced in both colorectal cancer cells and DCs. Likewise, specific ARI-induced histone methylation and acetylation changes marked epigenetically affected ISG promoters in both metastatic cancer cells and DCs. Analysis by ChIP-seq confirmed such ARI-induced epigenetically regulated IFN signature. The activation of this signal endowed DCs with a marked migratory capability. Our results establish a direct correlation between reexpression of silenced ISGs by epigenetic control and ARI anticancer activity and provide new knowledge for the development of innovative combined therapeutic strategies for colorectal cancer..

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

“…Such a functionally unique form of stress-driven RCD is now usually referred to as immunogenic cell death (ICD). 5 Cellular stressors that are associated with ICD encompass (but are not limited to): (1) obligate intracellular pathogens including multiple bacterial and viral species 6-8 ; (2) therapeutic oncolytic viruses [9][10][11][12][13][14][15][16] ; (3) various molecules with oncolytic potential [17][18][19] ; (4) conventional chemotherapeutics such as numerous anthracyclines (ie, doxorubicin, epirubicin, idarubicin and mitoxantrone), some (but importantly not all) DNA-damaging agents (ie, cyclophosphamide and oxaliplatin, but not cisplatin), poly-A-ribose polymerase (PARP) inhibitors, mitotic poisons (ie, docetaxel and patupilone) and proteasomal inhibitors (ie, bortezomib and carfilzomib) [20][21][22][23][24][25] ; (5) epigenetic modifiers including DNA methyltransferase, histone deacetylase (HDAC) and bromodomain inhibitors [26][27][28][29][30] ; (6) targeted anticancer agents such as the tyrosine kinase inhibitor crizotinib, the epidermal growth factor receptor (EGFR)-specific monoclonal antibody cetuximab, the cyclin-dependent kinase (CDK) inhibitor dinaciclib and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib [31][32][33] ; (7) other chemicals including…”

Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer

“…High demethylation rate was detected in TT-RCC and PB-RCC vs HD derived Treg cells ( P <0,001) (Figure 5A ). As reference sequence the methylation of CpG sequences of IFN transcription regulatory factors 8 (IRF8) was considered [ 14 , 15 ]. Moreover to evaluate Tregs function culture supernatants were evaluated for IFN-γ and TGF-β1 on day 5 of cocolture.…”

“…Herein we show that TSDR demethylation increases in RCC isolated Tregs suggesting a higher suppressive function compared to healthy donors isolated Tregs. These results were compared to the demethylation induced by DNMTi azacytidine (AZA) and IFN-γ on unrelated sequence in the promoter of the Interferon Regulated Factor IRF-8 [ 14 , 15 ]. Tregs from RCC patients express higher CXCR4 compared with Tregs from healthy donors.…”

The Natural Agonist of Estrogen Receptor β Silibinin Plays an Immunosuppressive Role Representing a Potential Therapeutic Tool in Rheumatoid Arthritis

“…Total RNA was extracted from cells using the RNeasy Mini kit (Qiagen, Milan, Italy). RNA was DNase-I digested (Roche) and reverse transcribed as previously described ( 35 ). Quantitative PCR was performed in duplicate by the real-time fluorescence detection method with the fluorescent DNA binding dye SYBR green (Power SYBR Green PCR master kit; Applied Biosystems) by using an ABI PRISM 7900 (Applied Biosystems).…”