Abstract B025: Multi-omic characterisation of the immune microenvironment in Rhabdoid Tumours

IF 16.6 1区 医学 Q1 ONCOLOGY
Erin Coll, Chelsea Mayoh, Lauren Brown, Anne-Lise Gerard, Helen McGuire, Paul Ekert
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引用次数: 0

Abstract

The University of Sydney, Sydney, NSWRhabdoid Tumours (RTs) are highly aggressive rare pediatric malignancies that primarily affect infants and young children, arising as malignant Rhabdoid Tumours (MRTs) in the kidney or Atypical Teratoid/Rhabdoid Tumours (AT/RTs) in the brain. These tumours are driven by SMARCB1 mutations or deletions and exhibit a low tumour mutation burden (TMB), traditionally suggesting poor immunogenicity. However, immune profiling has revealed substantial immune infiltration into the tumour immune microenvironment (TIME), including robust T-cell and myeloid cell presence, PD-L1 expression, and SMARCB1-dependent re-expression of endogenous retroviruses (ERVs), which can activate anti-tumour immune responses. Despite these features, RTs remain incurable, underscoring the need to elucidate their immune landscape to inform novel therapeutic strategies. Using data from the ZERO Childhood Cancer program, we applied bulk RNA sequencing and whole-genome sequencing to deconvolute the immune cell composition beyond T cells, preform IPASS, and assess associations between genomic alterations and immune features. Notably, we identified a strong correlation between high inflammation/IPASS scores and pathogenic SWI/SNF complex mutations, including SMARCB1 loss. Among immune modulators, leukemia inhibitory factor (LIF) emerged as a key player, displaying high expression in RTs and an inverse relationship with SWI/SNF gene expression. To spatially resolve the TIME of RTs, we performed spatial transcriptomics and proteomics, focusing on immune cell infiltration and exclusion mechanisms mediated by LIF-LIFR signalling. We found that LIF is predominantly expressed by tumour cells, while LIFR is enriched on myeloid cells, suggesting a tumour-driven immunosuppressive axis. Moreover, MRTs and AT/RTs exhibit distinct immune architectures: MRTs are highly inflamed, with dispersed T cells and myeloid cells across tumour and stromal regions, whereas AT/RTs are dominated by myeloid infiltration localized to stromal regions and perivascular niches. Xenium-based differential gene expression analysis of macrophages from AT/RT and MRT patients reveals that AT/RT-associated macrophages exhibit reduced interferon signalling and proliferation, but enhanced tissue remodelling and immunosuppressive M2-like polarization. This study underscores the power of multiomic approaches in dissecting the immune landscape of rare and incurable paediatric solid tumours. By leveraging the IPASS gene signature and LIF-LIFR axis, we identified immune exclusion mechanisms that could serve as therapeutic targets. Future investigations will focus on validating these findings and assessing their potential for combinatorial immunotherapies in rhabdoid tumours. Lastly, the dataset generated by this study is a rare and invaluable resource in the advancement of rhabdoid tumour research. Citation Format: Erin Coll, Chelsea Mayoh, Lauren Brown, Anne-Lise Gerard, Helen McGuire, Paul Ekert. Multi-omic characterisation of the immune microenvironment in Rhabdoid Tumours [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr B025.
B025:横纹肌样肿瘤免疫微环境的多组学特征
NSWRhabdoid tumors (RTs)是一种高度侵袭性的罕见儿科恶性肿瘤,主要影响婴儿和幼儿,以肾脏恶性横纹肌样肿瘤(MRTs)或脑非典型畸胎瘤/横纹肌样肿瘤(AT/RTs)的形式出现。这些肿瘤由SMARCB1突变或缺失驱动,并表现出低肿瘤突变负担(TMB),传统上表明免疫原性差。然而,免疫分析显示大量的免疫渗透到肿瘤免疫微环境(TIME)中,包括强大的t细胞和骨髓细胞的存在、PD-L1的表达和内源性逆转录病毒(erv)的smarcb1依赖性的再表达,这可以激活抗肿瘤免疫反应。尽管有这些特点,RTs仍然是无法治愈的,强调需要阐明其免疫景观,以告知新的治疗策略。利用ZERO儿童癌症项目的数据,我们应用了大量RNA测序和全基因组测序来解卷积T细胞以外的免疫细胞组成,预形成IPASS,并评估基因组改变与免疫特征之间的关联。值得注意的是,我们发现高炎症/IPASS评分与致病性SWI/SNF复合物突变(包括SMARCB1丢失)之间存在很强的相关性。在免疫调节剂中,白血病抑制因子(leukemia inhibitory factor, LIF)在RTs中高表达,与SWI/SNF基因表达呈负相关,是一个关键角色。为了在空间上解析RTs的时间,我们进行了空间转录组学和蛋白质组学研究,重点研究了由lifr - lifr信号介导的免疫细胞浸润和排斥机制。我们发现LIF主要在肿瘤细胞中表达,而LIFR在髓细胞中富集,提示存在肿瘤驱动的免疫抑制轴。此外,mrt和AT/RTs表现出不同的免疫结构:mrt高度炎症,T细胞和骨髓细胞分散在肿瘤和间质区域,而AT/RTs主要是骨髓浸润局限于间质区域和血管周围壁龛。基于xenium的AT/RT和MRT患者巨噬细胞差异基因表达分析显示,AT/RT相关巨噬细胞表现出干扰素信号传导和增殖减少,但组织重塑和免疫抑制m2样极化增强。这项研究强调了多组学方法在解剖罕见和无法治愈的儿科实体肿瘤的免疫景观中的作用。通过利用IPASS基因标记和liff - lifr轴,我们确定了可以作为治疗靶点的免疫排斥机制。未来的研究将集中在验证这些发现和评估它们在横纹肌样肿瘤组合免疫治疗中的潜力。最后,本研究生成的数据集是推进横纹肌样肿瘤研究的一种罕见而宝贵的资源。引文格式:Erin Coll, Chelsea Mayoh, Lauren Brown, Anne-Lise Gerard, Helen McGuire, Paul Ekert。横纹肌样肿瘤免疫微环境的多组学特征[摘要]。AACR癌症研究特别会议论文集:儿童癌症的发现和创新-从生物学到突破性疗法;2025年9月25日至28日;波士顿,MA。费城(PA): AACR;癌症研究2025;85(18_Suppl_2): nr B025。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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