Stroma-infiltrating T cell spatiotypes define immunotherapy outcomes in adolescent and young adult patients with melanoma

Xinyu Bai, Grace H. Attrill, Tuba N. Gide, Peter M. Ferguson, Kazi J. Nahar, Ping Shang, Ismael A. Vergara, Umaimainthan Palendira, Ines Pires Silva, Matteo S. Carlino, Alexander M. Menzies, Georgina V. Long, Richard A. Scolyer, James S. Wilmott and Camelia Quek ()
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Xinyu Bai: The University of Sydney
Grace H. Attrill: The University of Sydney
Tuba N. Gide: The University of Sydney
Peter M. Ferguson: The University of Sydney
Kazi J. Nahar: The University of Sydney
Ping Shang: The University of Sydney
Ismael A. Vergara: The University of Sydney
Umaimainthan Palendira: The University of Sydney
Ines Pires Silva: The University of Sydney
Matteo S. Carlino: The University of Sydney
Alexander M. Menzies: The University of Sydney
Georgina V. Long: The University of Sydney
Richard A. Scolyer: The University of Sydney
James S. Wilmott: The University of Sydney
Camelia Quek: The University of Sydney

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The biological underpinnings of therapeutic resistance to immune checkpoint inhibitors (ICI) in adolescent and young adult (AYA) melanoma patients are incompletely understood. Here, we characterize the immunogenomic profile and spatial architecture of the tumor microenvironment (TME) in AYA (aged ≤ 30 years) and older adult (aged 31–84 years) patients with melanoma, to determine the AYA-specific features associated with ICI treatment outcomes. We identify two ICI-resistant spatiotypes in AYA patients with melanoma showing stroma-infiltrating lymphocytes (SILs) that are distinct from the adult TME. The SILhigh subtype was enriched in regulatory T cells in the peritumoral space and showed upregulated expression of immune checkpoint molecules, while the SILlow subtype showed a lack of immune activation. We establish a young immunosuppressive melanoma score that can predict ICI responsiveness in AYA patients and propose personalized therapeutic strategies for the ICI-resistant subgroups. These findings highlight the distinct immunogenomic profile of AYA patients, and individualized TME features in ICI-resistant AYA melanoma that require patient-specific treatment strategies.

Date: 2024
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DOI: 10.1038/s41467-024-47301-9

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