Reply to Haffner et al.: DNA hypomethylation renders tumors more immunogenic

Stone, Maureen; Chiappinelli, Katherine B.; Li, Huili; Murphy, Lauren; Travers, Meghan; Topper, Michael J.; Mathios, Dimitrios; Lim, Michael; Shih, Ie Ming; Wang, Tian Li; Hung, Chien Fu; Bhargava, Vipul; Wiehagen, Karla R.; Cowley, Glenn S.; Strick, Reiner; Strissel, Pamela L.; Baylin, Stephen B.; Zahnow, Cynthia A.

doi:10.1073/pnas.1811015115

Cited by 7 publications

(7 citation statements)

References 11 publications

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“…The drivers of the immune microenvironment in ovarian cancer remain unclear, although the extent of immune cell infiltration is strongly prognostic (13). Here we investigated whether modulation of epigenetic pathways could augment immune cell infiltration in high grade serous carcinoma (HGSC), the commonest subtype of ovarian cancer in light of previous data suggesting that epigenetic mechanisms could underpin immune evasion in ovarian cancer (4,43).…”

Section: Discussionmentioning

confidence: 99%

Dual G9A/EZH2 Inhibition Stimulates Antitumor Immune Response in Ovarian High-Grade Serous Carcinoma

Spiliopoulou

Spear

Mirza

et al. 2022

Molecular Cancer Therapeutics

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Ovarian high-grade serous carcinoma (HGSC) prognosis correlates directly with presence of intratumoral lymphocytes. However, cancer immunotherapy has yet to achieve meaningful survival benefit in patients with HGSC. Epigenetic silencing of immunostimulatory genes is implicated in immune evasion in HGSC and re-expression of these genes could promote tumour immune clearance. We discovered that simultaneous inhibition of the histone methyltransferases G9A and EZH2 activates the CXCL10-CXCR3 axis and increases homing of intratumoral effector lymphocytes and natural killer cells whilst suppressing tumour-promoting FoxP3 + CD4 T cells. The dual G9A/EZH2 inhibitor HKMTI-1-005 induced chromatin changes that resulted in the transcriptional activation of immunostimulatory gene networks, including the re-expression of elements of the ERV-K endogenous retroviral family.Importantly, treatment with HKMTI-1-005 improved the survival of mice bearing Trp53 -/null ID8 ovarian tumours and resulted in tumour burden reduction. These results indicate that inhibiting G9A and EZH2 in ovarian cancer alters the immune microenvironment and reduces tumour growth and therefore positions dual inhibition of G9A/EZH2 as a strategy for clinical development.Research.

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Section: Discussionmentioning

confidence: 99%

Dual G9A/EZH2 Inhibition Stimulates Antitumor Immune Response in Ovarian High-Grade Serous Carcinoma

Spiliopoulou

Spear

Mirza

et al. 2022

Molecular Cancer Therapeutics

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“…The profound hypomethylation of seminoma DNA, correlating also with the abundance of CD8+ cells, was associated with significant expression of human endogenous retroviruses as well as an increase in IFN-α1. Subsequently, activation of type I IFN signaling, as a consequence of the activity of hypomethylating agents, resulted in a more immunogenic phenotype of these tumors (54).…”

Section: Combining Of Hypomethylating Agents With Immunotherapymentioning

confidence: 99%

Immunotherapy in Testicular Germ Cell Tumors

et al. 2020

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Testicular germ cell tumors (TGCTs) are malignancies with very high curative potential even in metastatic settings, mainly due to the introduction of cisplatin in the treatment of this disease. However, in a group of patients with cisplatin-refractory disease or with progressive disease despite high-dose salvage chemotherapy treatment, the prognosis is typically dismal. The triple combination of gemcitabine, oxaliplatin, and paclitaxel (GOP) has reasonable efficacy and is considered to be standard care for this group of patients. It remains to be seen, however, whether refractory TGCTs may represent a potential target for immune checkpoint inhibition. This review will focus on the rationale of the use of immunotherapy for platinum-refractory TGCTs and summarize data reporting experiences with immune checkpoint inhibitor treatment for this malignancy.

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“…Furthermore, the interesting concept of DNA demethylation as an important factor in overcoming cisplatin resistance was proposed by Albany et al ., (). Hypomethylating agents also render tumours more immunogenic via activating the type‐I IFN signalling (Stone et al ., ). Seminoma is constitutively hypomethylated tumour; therefore, Haffner et al .…”

Section: Emerging Immune Biomarkers and Immunotherapy In Gctsmentioning

confidence: 97%

Immune mechanisms and possible immune therapy in testicular germ cell tumours

2019

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Background: Testicular germ cell tumours (GCTs) are the only universally curable solid malignancy. The long-term cure rate of >95% is attributed to the extraordinary sensitivity to cisplatin-based treatment but a proportion of patients die due to a progression of the chemotherapy-refractory disease. While treatment of a variety of solid cancers was significantly improved with recent immune therapies, the immunology and immunotherapy remained underinvestigated in GCTs. Objectives: In this narrative review, we summarize evidence about immune-related mechanisms and possible immune therapies in GCTs and provide insights and implications for future research and clinical practice. Materials and methods: We performed a comprehensive search of PubMed/MEDLINE to identify original and review articles reporting on immune mechanisms and immunotherapy in GCTs. Review articles were further searched for additional original articles. Results: Clear link of immune surveillance and the presence of GCT have been identified with several novel immune-related prognostic biomarkers published recently. Several case reports, case series, and preliminary results from phase I-II studies are emerging to report on the efficacy of immune checkpoint inhibitors. Discussion: Newly discovered immune biomarkers provide an evidence supporting the role of immune environment in the GCT biology. While these discoveries provide only an initial insight into the immunobiology, strong correlation with prognosis is evident. This provided a premise to investigate the treatment efficacy of novel immunotherapy. Some efficacy of these treatments has been reported in clinical setting; however, the results of published studies with immune checkpoint inhibitor monotherapy seem to be disappointing. Conclusion: Immune-related mechanisms and efficacy of immune checkpoint blockade in GCTs should be further investigated in preclinical and clinical studies.

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Reply to Haffner et al.: DNA hypomethylation renders tumors more immunogenic

Cited by 7 publications

References 11 publications

Dual G9A/EZH2 Inhibition Stimulates Antitumor Immune Response in Ovarian High-Grade Serous Carcinoma

Dual G9A/EZH2 Inhibition Stimulates Antitumor Immune Response in Ovarian High-Grade Serous Carcinoma

Immunotherapy in Testicular Germ Cell Tumors

Immune mechanisms and possible immune therapy in testicular germ cell tumours

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