RECQL4 affects MHC class II‐mediated signalling and favours an immune‐evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma
Abstract Background Cancer immunotherapy has transformed metastatic cancer treatment, yet challenges persist regarding therapeutic efficacy. RECQL4, a RecQ‐like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy...
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2025-01-01
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| Online Access: | https://doi.org/10.1002/ctm2.70094 |
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| author | Sara Egea‐Rodriguez Renáta Váraljai Thierry M. Nordmann Restuan Lubis Manuel Philip Florian Rambow Alexander Roesch Michael Flaig Susanne Horn Raphael Stoll Fang Zhao Annette Paschen Bert Klebl Ian D. Hickson Dirk Schadendorf Matthias Mann Iris Helfrich |
| author_facet | Sara Egea‐Rodriguez Renáta Váraljai Thierry M. Nordmann Restuan Lubis Manuel Philip Florian Rambow Alexander Roesch Michael Flaig Susanne Horn Raphael Stoll Fang Zhao Annette Paschen Bert Klebl Ian D. Hickson Dirk Schadendorf Matthias Mann Iris Helfrich |
| author_sort | Sara Egea‐Rodriguez |
| collection | DOAJ |
| description | Abstract Background Cancer immunotherapy has transformed metastatic cancer treatment, yet challenges persist regarding therapeutic efficacy. RECQL4, a RecQ‐like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy of immune checkpoint inhibitor (ICI) therapies. However, its role in patient response to ICI remains unclear. Methods We analysed whole exome and bulk RNA sequencing data from a pan‐cancer cohort of 25 775 patients and cutaneous melanoma cohorts (untreated: n = 471, anti‐progressive disease [PD]‐1 treated: n = 212). RECQL4 copy number variations and expression levels were assessed for patient outcomes. We performed gene set enrichment analysis to identify RECQL4‐dependent signalling pathways and explored the association between RECQL4 levels and immunoscores. We evaluated the interplay of ICI response and RECQL4 expression in melanoma cohorts of 95 responders and 85 non‐responders prior to and after ICI‐targeted therapy and tested the prognostic power of RECQL4. Finally, we generated genetically engineered RECQL4 variants and conducted comprehensive multi‐omic profiling, employing techniques such as liquid chromatography with tandem mass spectrometry, to elucidate mechanistic insights. Results We identified RECQL4 as a critical negative regulator of poor prognosis and response to ICI therapy, but also demonstrated its suitability as an independent biomarker in melanoma. High tumour purity and limited signatures of tumour immunogenicity associated with response to anti‐PD‐1 correlated with high RECQL4 activity. We found alterations in the secretion profile of immune regulatory factors and immune‐related pathways robustly suppressed in tumours with high RECQL4 levels, underscoring its crucial role in fostering immune evasion. Mechanistically, we identified RECQL4‐mediated regulation of major histocompatibility complex class II molecule expression and uncovered class II major histocompatibility complex transactivator as a mediator bridging this regulation. Conclusions Our findings unraveled the pivotal role of RECQL4 in immune modulation and its potential as both a predictive biomarker and therapeutic target for optimising immunotherapeutic strategies across various cancer types. Highlights High RECQL4 expression limits survival and can act as an independent prognostic factor in melanoma patients. RECQL4 has the potential to act as a negative feedback mediator of immune checkpoint‐targeted therapy by limiting signatures associated with therapeutic efficacy. RECQL4 favours an immune‐evasive phenotype by downregulating major histocompatibility complex class II molecules. |
| format | Article |
| id | doaj-art-e621d224bc9d4504bcb43d6b08328bbc |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-e621d224bc9d4504bcb43d6b08328bbc2025-01-25T04:00:38ZengWileyClinical and Translational Medicine2001-13262025-01-01151n/an/a10.1002/ctm2.70094RECQL4 affects MHC class II‐mediated signalling and favours an immune‐evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanomaSara Egea‐Rodriguez0Renáta Váraljai1Thierry M. Nordmann2Restuan Lubis3Manuel Philip4Florian Rambow5Alexander Roesch6Michael Flaig7Susanne Horn8Raphael Stoll9Fang Zhao10Annette Paschen11Bert Klebl12Ian D. Hickson13Dirk Schadendorf14Matthias Mann15Iris Helfrich16Department of Dermatology and Allergy University Hospital of Munich Ludwig‐Maximilian‐University Munich GermanySkin Cancer Unit of the Dermatology Department Medical Faculty West German Cancer Center University Duisburg‐Essen Essen GermanyProteomics and Signal Transduction Max Planck Institute of Biochemistry Martinsried GermanyLead Discovery Center GmbH Dortmund GermanySkin Cancer Unit of the Dermatology Department Medical Faculty West German Cancer Center University Duisburg‐Essen Essen GermanyDepartment of Applied Computational Cancer Research Institute for AI in Medicine (IKIM) University Hospital Essen University Duisburg‐Essen Essen GermanySkin Cancer Unit of the Dermatology Department Medical Faculty West German Cancer Center University Duisburg‐Essen Essen GermanyDepartment of Dermatology and Allergy University Hospital of Munich Ludwig‐Maximilian‐University Munich GermanyRudolf Schönheimer Institute of Biochemistry Medical Faculty of the University of Leipzig Leipzig GermanyBiomolecular Spectroscopy and RUBiospec NMR, Faculty of Chemistry and Biochemistry Ruhr University of Bochum Bochum GermanySkin Cancer Unit of the Dermatology Department Medical Faculty West German Cancer Center University Duisburg‐Essen Essen GermanySkin Cancer Unit of the Dermatology Department Medical Faculty West German Cancer Center University Duisburg‐Essen Essen GermanyLead Discovery Center GmbH Dortmund GermanyCenter for Chromosome Stability Department of Cellular and Molecular Medicine University of Copenhagen Copenhagen N DenmarkSkin Cancer Unit of the Dermatology Department Medical Faculty West German Cancer Center University Duisburg‐Essen Essen GermanyProteomics and Signal Transduction Max Planck Institute of Biochemistry Martinsried GermanyDepartment of Dermatology and Allergy University Hospital of Munich Ludwig‐Maximilian‐University Munich GermanyAbstract Background Cancer immunotherapy has transformed metastatic cancer treatment, yet challenges persist regarding therapeutic efficacy. RECQL4, a RecQ‐like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy of immune checkpoint inhibitor (ICI) therapies. However, its role in patient response to ICI remains unclear. Methods We analysed whole exome and bulk RNA sequencing data from a pan‐cancer cohort of 25 775 patients and cutaneous melanoma cohorts (untreated: n = 471, anti‐progressive disease [PD]‐1 treated: n = 212). RECQL4 copy number variations and expression levels were assessed for patient outcomes. We performed gene set enrichment analysis to identify RECQL4‐dependent signalling pathways and explored the association between RECQL4 levels and immunoscores. We evaluated the interplay of ICI response and RECQL4 expression in melanoma cohorts of 95 responders and 85 non‐responders prior to and after ICI‐targeted therapy and tested the prognostic power of RECQL4. Finally, we generated genetically engineered RECQL4 variants and conducted comprehensive multi‐omic profiling, employing techniques such as liquid chromatography with tandem mass spectrometry, to elucidate mechanistic insights. Results We identified RECQL4 as a critical negative regulator of poor prognosis and response to ICI therapy, but also demonstrated its suitability as an independent biomarker in melanoma. High tumour purity and limited signatures of tumour immunogenicity associated with response to anti‐PD‐1 correlated with high RECQL4 activity. We found alterations in the secretion profile of immune regulatory factors and immune‐related pathways robustly suppressed in tumours with high RECQL4 levels, underscoring its crucial role in fostering immune evasion. Mechanistically, we identified RECQL4‐mediated regulation of major histocompatibility complex class II molecule expression and uncovered class II major histocompatibility complex transactivator as a mediator bridging this regulation. Conclusions Our findings unraveled the pivotal role of RECQL4 in immune modulation and its potential as both a predictive biomarker and therapeutic target for optimising immunotherapeutic strategies across various cancer types. Highlights High RECQL4 expression limits survival and can act as an independent prognostic factor in melanoma patients. RECQL4 has the potential to act as a negative feedback mediator of immune checkpoint‐targeted therapy by limiting signatures associated with therapeutic efficacy. RECQL4 favours an immune‐evasive phenotype by downregulating major histocompatibility complex class II molecules.https://doi.org/10.1002/ctm2.70094immune evasionimmunotherapymelanomaMHC class IIRECQL4 |
| spellingShingle | Sara Egea‐Rodriguez Renáta Váraljai Thierry M. Nordmann Restuan Lubis Manuel Philip Florian Rambow Alexander Roesch Michael Flaig Susanne Horn Raphael Stoll Fang Zhao Annette Paschen Bert Klebl Ian D. Hickson Dirk Schadendorf Matthias Mann Iris Helfrich RECQL4 affects MHC class II‐mediated signalling and favours an immune‐evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma Clinical and Translational Medicine immune evasion immunotherapy melanoma MHC class II RECQL4 |
| title | RECQL4 affects MHC class II‐mediated signalling and favours an immune‐evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma |
| title_full | RECQL4 affects MHC class II‐mediated signalling and favours an immune‐evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma |
| title_fullStr | RECQL4 affects MHC class II‐mediated signalling and favours an immune‐evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma |
| title_full_unstemmed | RECQL4 affects MHC class II‐mediated signalling and favours an immune‐evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma |
| title_short | RECQL4 affects MHC class II‐mediated signalling and favours an immune‐evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma |
| title_sort | recql4 affects mhc class ii mediated signalling and favours an immune evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma |
| topic | immune evasion immunotherapy melanoma MHC class II RECQL4 |
| url | https://doi.org/10.1002/ctm2.70094 |
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