Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a<i>TP53</i>-Dependent Manner

McDonald, James I.; Diab, Noor; Arthofer, Elisa; Hadley, Melissa; Kanholm, Tomas; Rentia, Uzma; Gomez, Stephanie; Yu, Angela; Grundy, Erin E.; Cox, Olivia L.; Topper, Michael J.; Strissel, Pamela L.; Strick, Reiner; Wang, Ting; Baylin, Stephen B.; Chiappinelli, Katherine B.

doi:10.1158/0008-5472.can-20-4243

Cited by 19 publications

(25 citation statements)

References 68 publications

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“…It has been reported that HMAs could cause the reexpression of endogenous retroviruses, which in turn trigger an IFN response ( 7 ). The transcriptomes of 9 paired specimens obtained before and after treatment were analyzed for differential expression of transposable elements (TEs) (see Supplemental Methods ) ( 21 , 22 ). We found that 21 TEs were differentially expressed between pre- and post-treatment specimens (FDR <0.05; Supplemental Table 8 ), supporting the idea that changes in the expression of retroviral elements are detectable in human tissue after HMA treatment.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer

Chen

Xie

Cowan

et al. 2022

Journal of Clinical Investigation

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Background Immune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study. Methods Eligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m 2 ) on days 1–4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment. Results Among 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%–49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4 + T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8 + T cells and CD20 + B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR. Conclusion Epigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC. Trial registration ClinicalTrials.gov NCT02901899. Funding US Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.

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Section: Resultsmentioning

confidence: 99%

Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer

Chen

Xie

Cowan

et al. 2022

Journal of Clinical Investigation

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“…Classon and colleagues implicated a specific H3K9 methylase, known to be critical for heterochromatin formation and maintenance (134). Chiappinelli et al reported increase in repeat element expression, another component in heterochromatic silenced regions (135). Finally, other studies implicate PRC2 and EZH2 in a similar mechanism (48, 136).…”

Section: Discussionmentioning

confidence: 99%

CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape

Alamoudi

Chipman

Deleso-Frechette³

et al. 2022

Preprint

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Triple negative breast cancers (TNBC) pose exceptional challenges with fatal brain metastases as a clear and unmet need. Immune checkpoint inhibitors (ICIs) are promising therapeutic strategies, but most TNBC are resistant, or cold tumors, due to lack of tumor-resident immune engagement. No FDA-approved therapies exist which promote a cold-to-hot transition or induce the important biomarker PD-L1, often used for ICI clinical decision-making. Maximal ICI susceptibility, or a full cold-to-hot transition, requires reciprocal Wnt signaling inhibition and Jak/STAT/interferon signaling activation. We report a new compound combination (CHA1) that fits the above criteria. CHA1 is comprised of EGCG (epigallocatechin-3-gallate; green-tea compound) and decitabine (DNA-methyltransferase (DNMT1) inhibitor; 5-deaza-cytidine; FDA-approved for hematologic malignancies). We used immune-compromised and syngeneic TNBC pre-clinical models to investigate tumor-intrinsic and tumor-resident T-cell effects, respectively. All results required CHA1 (but not EGCG or decitabine alone) and utilized attainable human dose equivalences with manageable safety profiles. CHA1 triggered efficient Wnt signaling inhibition by elevating Wnt pathway inhibitors (HBP1 and SFRP1) and traversed the blood-brain barrier to reduce both tumor and brain metastatic growth. Transcriptomic and expression analyses revealed that CHA1 treatment effectuated a robust tumor-intrinsic JAK/STAT/IFN response 1) to induce PDL1 and 2) to induce antigen presentation and processing genes, including MHC-1, MHC-2 and numerous genes attributed to professional antigen-presenting cells; 3) to induce CD8+-T-cell infiltration and activation. Additionally, CHA1 pre-treatment improved anti-PDL1 efficacy in a syngeneic setting. Lastly, we derived a composite gene signature emblematic of CHA1 treatment and of a favorable clinical prognosis in-silico. Together, our work supports a model in which CHA1 influences epigenetics, Wnt and Jak/STAT/IFN signaling mechanisms, all to reprogram an epithelial-mesenchymal TNBC tumor to express antigen-presenting properties and to recruit and activate tumor-resident CD8+-T-cells. We discuss our findings in the context of cancer biology and immunity with implications for improving ICI susceptibility for TNBC.

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“…10 DNMTis remove the repressive methylation marks that silence DNA, allowing for transcription of transposable elements (TEs) that can form immunogenic double-stranded (ds)RNAs. [11][12][13][14][15] Interestingly, this DNMTi treatment of OC cells alters immunogenic dsRNA expression in a TP53-dependent manner. 13 We previously showed that cell lines with TP53 mutations have significantly higher baseline expression of immunogenic dsRNAs.…”

Section: Open Accessmentioning

confidence: 99%

“…[11][12][13][14][15] Interestingly, this DNMTi treatment of OC cells alters immunogenic dsRNA expression in a TP53-dependent manner. 13 We previously showed that cell lines with TP53 mutations have significantly higher baseline expression of immunogenic dsRNAs. Additionally, p53 activation increased expression of these immunogenic dsRNAs by binding directly to the TE loci.…”

Section: Open Accessmentioning

confidence: 99%

Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer

Gomez

Cox

Walker

et al. 2022

J Immunother Cancer

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BackgroundNovel therapies are urgently needed for ovarian cancer (OC), the fifth deadliest cancer in women. Preclinical work has shown that DNA methyltransferase inhibitors (DNMTis) can reverse the immunosuppressive tumor microenvironment in OC. Inhibiting DNA methyltransferases activate transcription of double-stranded (ds)RNA, including transposable elements. These dsRNAs activate sensors in the cytoplasm and trigger type I interferon (IFN) signaling, recruiting host immune cells to kill the tumor cells. Adenosine deaminase 1 (ADAR1) is induced by IFN signaling and edits mammalian dsRNA with an A-to-I nucleotide change, which is read as an A-to-G change in sequencing data. These edited dsRNAs cannot be sensed by dsRNA sensors, and thus ADAR1 inhibits the type I IFN response in a negative feedback loop. We hypothesized that decreasing ADAR1 editing would enhance the DNMTi-induced immune response.MethodsHuman OC cell lines were treated in vitro with DNMTi and then RNA-sequenced to measure RNA editing. Adar1 was stably knocked down in ID8Trp53-/-mouse OC cells. Control cells (shGFP) or shAdar1 cells were tested with mock or DNMTi treatment. Tumor-infiltrating immune cells were immunophenotyped using flow cytometry and cell culture supernatants were analyzed for secreted chemokines/cytokines. Mice were injected with syngeneic shAdar1 ID8Trp53-/-cells and treated with tetrahydrouridine/DNMTi while given anti-interferon alpha and beta receptor 1, anti-CD8, or anti-NK1.1 antibodies every 3 days.ResultsWe show that ADAR1 edits transposable elements in human OC cell lines after DNMTi treatment in vitro. Combining ADAR1 knockdown with DNMTi significantly increases pro-inflammatory cytokine/chemokine production and sensitivity to IFN-β compared with either perturbation alone. Furthermore, DNMTi treatment and Adar1 loss reduces tumor burden and prolongs survival in an immunocompetent mouse model of OC. Combining Adar1 loss and DNMTi elicited the most robust antitumor response and transformed the immune microenvironment with increased recruitment and activation of CD8+ T cells.ConclusionIn summary, we showed that the survival benefit from DNMTi plus ADAR1 inhibition is dependent on type I IFN signaling. Thus, epigenetically inducing transposable element transcription combined with inhibition of RNA editing is a novel therapeutic strategy to reverse immune evasion in OC, a disease that does not respond to current immunotherapies.

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Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in aTP53-Dependent Manner

Cited by 19 publications

References 68 publications

Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer

Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer

CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape

Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer

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