Epigenetic reprogramming of tumor cell–intrinsic STING function sculpts antigenicity and T cell recognition of melanoma
Open accessAbstract
Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell-based immunotherapies. Evidence suggests that activation of stimulator of interferon genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear. In this study, we asked whether this suppression is, in part, epigenetically regulated and whether it is indeed a driver of melanoma resistance to T cell-based immunotherapies. Using genome-wide DNA methylation profiling, we show that promoter hypermethylation of cGAS and STING genes mediates their coordinated transcriptional silencing and contributes to the widespread impairment of the STING signaling function in clinically-relevant human melanomas and melanoma cell lines. This suppression is reversible through pharmacologic inhibition of DNA methylation, which can reinstate functional STING signaling in at least half of the examined cell lines. Using a series of T cell recognition assays with HLA-matched human melanoma tumor-infiltrating lymphocytes (TIL), we further show that demethylation-mediated restoration of STING signaling in STING-defective melanoma cell lines can improve their antigenicity through the up-regulation of MHC class I molecules and thereby enhance their recognition and ki…
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Promoter hypermethylation of cGAS and STING leads to coordinated transcriptional silencing of these genes, suppressing STING signaling in human melanoma and melanoma cell lines.
“promoter hypermethylation of cGAS and STING leads to coordinated transcriptional silencing of these genes, thereby suppressing STING signaling in human melanoma and melanoma cell lines37.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [37]
STING signaling is impaired in human melanoma cell lines.
“we have also shown that there is a widespread impairment of STING signaling in human melanoma cell lines”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [37]
Similar effects of 5AZADC on STING, DNMT3A, and DNMT3B expression were observed in A375 and SK-MEL-28 human melanoma cell lines.
“Similar effects were observed in A375 and SK-MEL-28, two STINGlow human melanoma cell lines37 (Fig. 3f).”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [37]
Promoter hypermethylation-driven STING silencing was found in two distinct murine melanoma cell lines.
“Consistent with our previous findings in human melanoma37, we found promoter hypermethylation-driven STING silencing in two distinct murine melanoma cell lines.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [37]
In human melanoma cell lines, STING-mediated IFN-β induction can augment surface expression of MHC class I and render them better targets for cytotoxic CD8+ T cell recognition and killing.
“Indeed, we have previously shown that in human melanoma cell lines STING-mediated IFN-β induction can augment their surface expression of MHC class I and therefore render them better targets for cytotoxic CD8+ T cell recognition and killing29,37.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [37]
The ability to target and restore STING signaling in tumor cells using epigenetic modulators provides a rationale to explore whether epigenetic reprogramming of tumor cell-intrinsic STING activity can improve the therapeutic efficacy of STING agonists.
“Despite this common suppression, the ability to target and restore STING signaling in tumor cells using epigenetic modulators35,37 provides a rationale to explore whether epigenetic reprogramming of tumor cell-intrinsic STING activity can improve the therapeutic efficacy of STING agonists.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [37]
STING-dependent MHC class I upregulation in human and mouse melanoma cells following demethylation-mediated restoration of STING signaling can enhance both their antigenicity and susceptibility to lysis by CD8+ T cells.
“This finding also coincides with our observation of STING-dependent MHC class I upregulation in human and mouse melanoma cells following demethylation-mediated restoration of STING signaling which can enhance both their antigenicity and susceptibility to lysis by CD8+ T cells29,37.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [37]
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Epigenetic state determines the in vivo efficacy of STING agonist therapy
Falahat, R., Berglund, A., Perez-Villarroel, P., Putney, R. M., Hamaidi, I., Kim, S., Pilon-Thomas, S., Barber, G. N., & Mulé, J. J. (2023) · Nature Communications · doi:10.1038/s41467-023-37217-1 · Cited by 94 · see citing works
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- Authors
- Falahat, R., Berglund, A., Putney, R. M., Perez-Villarroel, P., Aoyama, S., Pilon-Thomas, S., Barber, G. N., & Mulé, J. J.
- Affiliations
- Moffitt Cancer Center (US)
- Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612;
- University of Miami (US)
- Corresponding author
- Mulé, James J.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2021-04-07
- Volume
- 118
- Issue
- 15
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC8053941
- OpenAlex
- W3152326806
- Cited by
- 190
- References
- 5
- Citations by year
- 2026: 40 · 2025: 42 · 2024: 34 · 2023: 40 · 2022: 28 · 2021: 6
- FWCI
- 10.07
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA184845, P50CA168536, R01CA148995, P30CA076292)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- STING signaling, melanoma, DNA methylation, epigenetic reprogramming, tumor antigenicity, MHC class I expression, tumor-infiltrating lymphocytes, tumor immune evasion, demethylation, immunotherapy resistance
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Humans, Melanoma, Membrane Proteins, Nucleotidyltransferases, T-Lymphocytes, Histocompatibility Antigens Class I, Lymphocytes, Tumor-Infiltrating, DNA Methylation, Epigenesis, Genetic, Cell Line, Tumor
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