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.
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.