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Updated: May 19, 2026
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Epigenetic remodelling of gene expression profiles of neoplastic and normal tissues: immunotherapeutic implications
S Coral1, A Covre, H J M G Nicolay
1Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
Background:
Epigenetic remodelling of cancer cells is an attractive therapeutic strategy and distinct DNA hypomethylating agents (DHA) are being actively evaluated in patients with hemopoietic or solid tumours. However, no studies have investigated the modulation of gene expression profiles (GEP) induced by DHA in transformed and benign tissues. Such information is mandatory to clarify the fine molecular mechanism(s) underlying the clinical efficacy of DHA, to identify appropriate therapeutic combinations, and to address safety issues related to their demethylating potential in normal tissues. Thus, utilising a syngeneic mouse model, we investigated the remodelling of GEP of neoplastic and normal tissues induced by systemic administration of DHA.
Methods:
The murine mammary carcinoma cells TS/A were injected s.c. into female BALB/c mice that were treated i.p. with four cycles of the DHA 5-aza-2'-deoxycytidine (5-AZA-CdR) at a fractioned daily dose of 0.75 mg kg(-1) (q8 h × 3 days, every week). Whole mouse transcriptomes were analysed by microarrays in neoplastic and normal tissues from control and treated mice. Results were processed by bioinformatic analyses.
Results:
In all, 332 genes were significantly (P ≤ 0.05; FC ≥ 4) modulated (294 up and 38 downregulated) in neoplastic tissues from 5-AZA-CdR-treated mice compared with controls. In decreasing order of magnitude, changes in GEP significantly (P ≤ 0.05) affected immunologic, transport, signal transduction, spermatogenesis, and G-protein-coupled receptor protein signalling pathways. Epigenetic remodelling was essentially restricted to tumour tissues, leaving substantially unaltered normal ones.
Conclusion:
The ability of 5-AZA-CdR to selectively target tumour GEP and its major impact on immune-related genes, strongly support the clinical use of DHA alone or combined with immunotherapeutic agents.
Insights
DNA hypomethylating agents (DHAs) selectively remodel gene expression profiles in tumors, impacting immune pathways. This epigenetic remodeling in cancer cells suggests potential for DHA use in combination therapies.
Area of Science:
- Epigenetics
- Cancer Biology
- Pharmacology
Background:
- Epigenetic remodeling is a promising cancer therapy strategy.
- DNA hypomethylating agents (DHAs) are under clinical evaluation.
- Understanding DHA-induced gene expression changes in tumors and normal tissues is crucial for efficacy and safety.
Purpose of the Study:
- To investigate gene expression profile (GEP) remodeling in neoplastic and normal tissues induced by systemic DHA administration.
- To clarify molecular mechanisms of DHA efficacy and safety.
Main Methods:
- A syngeneic mouse model with murine mammary carcinoma cells (TS/A) was used.
- Mice were treated with 5-aza-2'-deoxycytidine (5-AZA-CdR), a DHA.
- Whole transcriptome analysis via microarrays and bioinformatic analysis were performed on tumor and normal tissues.
Main Results:
- 332 genes were significantly modulated in tumor tissues of 5-AZA-CdR treated mice.
- Affected pathways included immunologic, transport, signal transduction, and G-protein-coupled receptor signaling.
- Epigenetic remodeling was largely confined to tumor tissues, with normal tissues remaining substantially unaltered.
Conclusions:
- 5-aza-2'-deoxycytidine (5-AZA-CdR) selectively targets tumor gene expression profiles.
- DHAs significantly impact immune-related genes, supporting their clinical use.
- DHAs show potential as monotherapy or in combination with immunotherapy.
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