Decitabine increases neoantigen and cancer testis antigen expression to enhance T-cell–mediated toxicity against glioblastoma

Abstract

Background Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Despite maximal treatment, median survival remains dismal at 14–24 months. Immunotherapies, such as checkpoint inhibition, have revolutionized management of some cancers but have little benefit for GBM patients. This is, in part, due to the low mutational and neoantigen burden in this immunogenically “cold” tumor. Methods U87MG and patient-derived cell lines were treated with 5-aza-2′-deoxycytidine (DAC) and underwent whole-exome and transcriptome sequencing. Cell lines were then subjected to cellular assays with neoantigen and cancer testis antigen (CTA) specific T cells. Results We demonstrate that DAC increases neoantigen and CTA mRNA expression through DNA hypomethylation. This results in increased neoantigen presentation by MHC class I in tumor cells, leading to increased neoantigen- and CTA-specific T-cell activation and killing of DAC-treated cancer cells. In addition, we show that patients have endogenous cancer-specific T cells in both tumor and blood, which show increased tumor-specific activation in the presence of DAC-treated cells. Conclusions Our work shows that DAC increases GBM immunogenicity and consequent susceptibility to T-cell responses in vitro. Our results support a potential use of DAC as a sensitizing agent for immunotherapy.

A Bioinformatic Approach Based on Systems Biology to Determine the Effects of SARS-CoV-2 Infection in Patients with Hypertrophic Cardiomyopathy

“…By boosting the activation of the mammalian target of rapamycin complex 2, rapamycin, another drug candidate discovered, may be used to reduce inflammation in patients with heart disease [ 66 ]. Meanwhile, another drug, decitabine, could increase neoantigen expression to enhance T cell-mediated toxicity against glioblastoma [ 67 ]. Testosterone enanthate replacement therapy is commonly used in patients with low testosterone [ 68 ].…”

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

“…Notably, clinical attempts to treat newly diagnosed and recurrent GBM with epigenetic inhibitors (plus chemoradiation and surgery) have had negligible anti-tumor effects compared to standard-of-care treatment alone ( 186 – 191 ). However, preclinical studies investigating the immune effects of epigenetic inhibitors demonstrate increased immunogenicity, indicating that combining epigenetic and immunostimulatory treatment modalities may have potent anti-tumor effects ( Table 3 ) ( 17 , 44 , 46 , 104 , 185 ). Two early phase clinical trials combining anti-PD1 checkpoint inhibitors with azacytidine (DNA methyltransferase inhibitor) or vorinostat (HDAC inhibitor) plus standard chemoradiation are currently underway in IDH-mutant gliomas (NCT03684811) and newly diagnosed GBM (NCT03426891), respectively.…”

“…Thus, strategies for targeting immune suppressive mechanism specifically within the TME while avoiding counterproductive systemic effects are needed. Despite these early phase results, the immunogenic effects of epigenetic inhibitors and combo epigenetic-immune therapy in preclinical GBM studies are promising ( 17 , 44 , 46 , 104 , 185 , 192 ) and deserve to be explored to their full extent in clinical trials. Notably, increased immune recognition and resultant cytolysis of tumor cells by T cells and NK cells has been achieved through HDAC inhibitors and DNA hypomethylating agents (e.g., decitabine) ( 44 , 46 , 104 , 185 ).…”

“…Despite these early phase results, the immunogenic effects of epigenetic inhibitors and combo epigenetic-immune therapy in preclinical GBM studies are promising ( 17 , 44 , 46 , 104 , 185 , 192 ) and deserve to be explored to their full extent in clinical trials. Notably, increased immune recognition and resultant cytolysis of tumor cells by T cells and NK cells has been achieved through HDAC inhibitors and DNA hypomethylating agents (e.g., decitabine) ( 44 , 46 , 104 , 185 ). Additionally, BRD4 inhibition attenuated an immunosuppressive GSC phenotype to enhance the anti-tumor immune response ( 17 ).…”

Therapeutic Strategies to Enhance Tumor Antigenicity: Making the Tumor Detectable by the Immune System

“…In addition to global demethylation, some studies point to DAC leading to the inhibition of NMD [ 101 ], which, as discussed earlier in this review, triggers the stabilization of aberrant mRNAs leading to the emergence of a potential array of neoantigens. Recently, a novel study showed that treatment with DAC in glioblastoma, a tumor with a really low TMB, induces the presentation of MHC-I-dependent neoantigens [ 102 ], demonstrating the high potential of epigenetic drugs in cancers with low mutational levels. The researchers treated patient-derived glioblastoma cells with DAC and co-cultured them with tumor-infiltrating lymphocytes (TILs) isolated from patients ex vivo, showing a significant immune reactivity boost when tumor cells were treated with DAC.…”