Background
The DNA helicase RECQL4 is involved in DNA replication, recombination, transcription and damage repair by unwinding various DNA structures. Components of the DNA repair machinery have been shown to influence response to immune checkpoint inhibitor (ICI) therapy in cancer patients. Therefore, we defined the impact of RECQL4 for melanoma progression and ICI efficacy.
Materials and Methods
We investigated how RECQL4 copy number levels affect patient progression using whole exome sequencing data in a pan-cancer cohort of 25,775 patients. In addition, gene set enrichment analysis revealed the pathways modulated by RECQL4 amplification. We also used the Proteome Profiler Human XL Cytokine Array and performed liquid chromatography (LC) tandem mass spectrometry (MS) to unravel the proteins altered by RECQL4 overexpression in A375 cell supernatant and lysates, respectively. We then analyzed bulk RNA sequencing data from cutaneous melanoma cohorts of untreated (n = 471) and anti-PD-1-treated (n = 212) patients. We calculated intra-tumoral immune cell infiltration using the xCELL algorithm and examined its correlation with RECQL4 levels. We also evaluated RECQL4 expression in responders (n = 95) versus non-responders (n = 86) to anti-PD-1 treatment. We evaluated the survival impact and prognostic power of RECQL4 using Kaplan-Meier and Cox proportional hazards model analyses.
Results
RECQL4 gene amplification directed the downregulation of multiple immune-related pathways, including IL-2 signaling, the complement cascade, or the IFN response, thereby reducing survival in melanoma patients. In addition, RECQL4 overexpression promoted immune evasion through the downregulation of MHC class II molecules. Furthermore, both RECQL4 copy number and expression levels correlated with decreased intratumoral numbers of CD4+ and CD8+ T cells, macrophages and dendritic cells, resulting in a reduced Tumor Immunogenicity Associated with Response to Anti-PD1 (TIARA-PD1) signature. Finally, we identified high RECQL4 expression as an independent prognostic factor for reduced survival and response to PD-1-targeted therapy in patients with cutaneous melanoma.
Conclusions
We have identified RECQL4 as a potential therapeutic target for the improvement of ICI therapy due to its role in immune evasion. This work was supported by the European Commission Horizon 2020 – Research and Innovation Framework Programme. Marie Skłodowska-Curie Innovative Training Networks – AntiHelix – Grant number: 859853 to I.H., B.K. and I.D.H.; the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 418179183 – KFO 337 (HE 5294/2-1 (IH), HO 6389/2-1 (SH), and Hiege Stiftung – Die Deutsche Hautkrebsstiftung (to I.H.).
S. Egea-Rodriguez: None. R. Váraljai: None. T.M. Nordmann: None. R. Lubis: None. M. Philip: None. F. Rambow: None. A. Roesch: None. D. Schadendorf: None. B. Klebl: None. I.D. Hickson: None. M. Mann: None. S. Horn: None. I. Helfrich: None.