Single-cell transcriptomics reveals immune suppression and cell states predictive of patient outcomes in rhabdomyosarcoma

Jeff DeMartino, Michael T. Meister, Lindy L. Visser, Mariël Brok, Marian J. A. Groot Koerkamp, Amber K. L. Wezenaar, Laura S. Hiemcke-Jiwa, Terezinha Souza, Johannes H. M. Merks, Anne C. Rios, Frank C. P. Holstege, Thanasis Margaritis () and Jarno Drost ()
Additional contact information
Jeff DeMartino: Princess Máxima Center for Pediatric Oncology
Michael T. Meister: Princess Máxima Center for Pediatric Oncology
Lindy L. Visser: Princess Máxima Center for Pediatric Oncology
Mariël Brok: Princess Máxima Center for Pediatric Oncology
Marian J. A. Groot Koerkamp: Princess Máxima Center for Pediatric Oncology
Amber K. L. Wezenaar: Princess Máxima Center for Pediatric Oncology
Laura S. Hiemcke-Jiwa: Princess Máxima Center for Pediatric Oncology
Terezinha Souza: Princess Máxima Center for Pediatric Oncology
Johannes H. M. Merks: Princess Máxima Center for Pediatric Oncology
Anne C. Rios: Princess Máxima Center for Pediatric Oncology
Frank C. P. Holstege: Princess Máxima Center for Pediatric Oncology
Thanasis Margaritis: Princess Máxima Center for Pediatric Oncology
Jarno Drost: Princess Máxima Center for Pediatric Oncology

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Paediatric rhabdomyosarcoma (RMS) is a soft tissue malignancy of mesenchymal origin that is thought to arise as a consequence of derailed myogenic differentiation. Despite intensive treatment regimens, the prognosis for high-risk patients remains dismal. The cellular differentiation states underlying RMS and how these relate to patient outcomes remain largely elusive. Here, we use single-cell mRNA sequencing to generate a transcriptomic atlas of RMS. Analysis of the RMS tumour niche reveals evidence of an immunosuppressive microenvironment. We also identify a putative interaction between NECTIN3 and TIGIT, specific to the more aggressive fusion-positive (FP) RMS subtype, as a potential cause of tumour-induced T-cell dysfunction. In malignant RMS cells, we define transcriptional programs reflective of normal myogenic differentiation and show that these cellular differentiation states are predictive of patient outcomes in both FP RMS and the less aggressive fusion-negative subtype. Our study reveals the potential of therapies targeting the immune microenvironment of RMS and suggests that assessing tumour differentiation states may enable a more refined risk stratification.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38886-8

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DOI: 10.1038/s41467-023-38886-8

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