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Epigenetic Treatment Alters Immune-Related Gene Signatures to Increase the Sensitivity of Anti PD-L1 Drugs
Chonji Fukumoto1,2, Pritam Sadhukhan1, Masahiro Shibata1,3
1Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Background/Objectives:
Head and neck squamous cell carcinoma (HNSCC) is the seventh most prevalent cancer worldwide. Despite intensive treatments, the prognosis is unfavorable. Recently, immunotherapy has emerged as a novel therapeutic strategy, and several immune-checkpoint blockade blockers provide clinical benefits to patients. However, the response rates of these antibodies are limited, and there is a pressing need to increase the efficacy of immunotherapy for HNSCC patients. Epigenetic treatment is emerging as a promising combination approach able to change immune-related gene signatures in tumors and potentially increase the efficacy of immunotherapy. In this study, we sought to elucidate further immune-related gene signatures altered through epigenetic treatment and explored whether epigenetic drugs can increase the efficacy of anti PD-L1 treatment in HNSCC.
Methods:
At first, we treated six HNSCC cell lines with 5-azacytidine and romidepsin and analyzed gene expression patterns by microarray and TaqMan arrays analysis. We then explored the therapeutic efficacy of epigenetic treatment with an anti PD-L1 antibody in a syngeneic mouse model.
Results:
Our microarray analysis revealed the differential expression of immune-related genes in cell lines treated with epigenetic drugs, as compared to untreated controls. Most importantly, these array analyses showed a significant change in the transcription of some immune related-and biologically relevant genes, such as HLA-DRA, HMOX1, IFI6, IL12A, IRF7, NFKB2, RPL3L, STAT1, STAT3, CSF1, CSF2, FAS, OASL, and PD-L1, after epigenetic treatment. Furthermore, the combination of epigenetic treatment with an anti PD-L1 antibody significantly suppressed tumor growth in a syngeneic mouse model. In vivo tumors treated with epigenetic drugs expressed higher STAT1, STAT3, and PD-L1 compared to untreated tumors. Increased PD-L1 expression is postulated to increase the efficacy of anti PD-L1 treatment.
Conclusions:
Our results highlight the importance of a combinational strategy employing both epigenetic and immunotherapy in HNSCC.
Insights
Combining epigenetic drugs with anti PD-L1 immunotherapy shows promise for head and neck squamous cell carcinoma (HNSCC). This approach alters immune gene expression and suppresses tumor growth, offering a potential strategy to improve HNSCC treatment outcomes.
Area of Science:
- Oncology
- Immunotherapy
- Epigenetics
Background:
- Head and neck squamous cell carcinoma (HNSCC) has an unfavorable prognosis despite current treatments.
- Immunotherapy, particularly immune-checkpoint blockade, offers benefits but has limited response rates in HNSCC.
- Epigenetic treatments are emerging as a strategy to enhance immunotherapy efficacy by modifying tumor immune gene expression.
Purpose of the Study:
- To identify immune-related gene signatures altered by epigenetic treatment in HNSCC.
- To investigate the potential of epigenetic drugs to enhance the efficacy of anti PD-L1 immunotherapy in HNSCC.
Main Methods:
- Six HNSCC cell lines were treated with 5-azacytidine and romidepsin.
- Gene expression patterns were analyzed using microarray and TaqMan arrays.
- The therapeutic efficacy of combining epigenetic treatment with an anti PD-L1 antibody was evaluated in a syngeneic mouse model.
Main Results:
- Epigenetic drug treatment significantly altered the expression of immune-related genes, including HLA-DRA, HMOX1, IL12A, STAT1, STAT3, and PD-L1.
- The combination of epigenetic treatment and anti PD-L1 antibody significantly suppressed tumor growth in vivo.
- Tumors treated with epigenetic drugs showed increased expression of STAT1, STAT3, and PD-L1, suggesting enhanced immunotherapy response.
Conclusions:
- Epigenetic treatment alters immune gene expression in HNSCC.
- Combining epigenetic therapy with anti PD-L1 immunotherapy is a promising strategy for HNSCC treatment.
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