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

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-01-15 DOI:10.1002/ctm2.70094

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

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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.

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RECQL4影响MHC ii类介导的信号传导，有利于免疫逃避信号，限制恶性黑色素瘤患者对免疫检查点抑制剂治疗的反应。

背景：癌症免疫疗法已经改变了转移性癌症的治疗，但治疗效果方面的挑战仍然存在。RECQL4是一种类似recq的解旋酶，作为DNA损伤反应的一部分，在DNA复制和修复中起着核心作用，这是一种涉及提高免疫检查点抑制剂（ICI）治疗效果的途径。然而，其在ICI患者反应中的作用尚不清楚。方法：我们分析了来自25775名泛癌症队列和皮肤黑色素瘤队列（未治疗：n = 471，抗进展性疾病[PD]-1治疗：n = 212）的全外显子组和大量RNA测序数据。评估RECQL4拷贝数变异和表达水平对患者预后的影响。我们进行了基因集富集分析，以确定RECQL4依赖的信号通路，并探索RECQL4水平与免疫评分之间的关系。我们评估了在ICI靶向治疗前后95名有反应者和85名无反应者的黑色素瘤队列中ICI反应和RECQL4表达的相互作用，并测试了RECQL4的预后能力。最后，我们生成了基因工程的RECQL4变体，并利用液相色谱和串联质谱等技术进行了全面的多组学分析，以阐明机制见解。结果：我们发现RECQL4是不良预后和对ICI治疗反应的关键负调节因子，但也证明了它作为黑色素瘤独立生物标志物的适用性。高肿瘤纯度和有限的肿瘤免疫原性特征与抗pd -1反应相关，与高RECQL4活性相关。我们发现，在高RECQL4水平的肿瘤中，免疫调节因子和免疫相关通路的分泌谱发生了改变，这表明它在促进免疫逃避中起着至关重要的作用。在机制上，我们发现了recql4介导的主要组织相容性复合体II类分子表达的调节，并发现了II类主要组织相容性复合体反激活子作为连接这种调节的中介。结论：我们的研究结果揭示了RECQL4在免疫调节中的关键作用，以及它作为一种预测性生物标志物和治疗靶点的潜力，可以优化各种癌症类型的免疫治疗策略。重点：高RECQL4表达限制了黑色素瘤患者的生存，并且可以作为一个独立的预后因素。RECQL4有可能通过限制与治疗效果相关的特征，作为免疫检查点靶向治疗的负反馈介质。RECQL4通过下调主要组织相容性复合体II类分子，有利于免疫逃避表型。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.