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 da Silva; Matteo S Carlino; Alexander M Menzies; Georgina V Long; Richard A Scolyer; James S Wilmott; Camelia Quek

doi:10.1038/s41467-024-47301-9

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

Nat Commun. 2024 Apr 8;15(1):3014. doi: 10.1038/s41467-024-47301-9.

Authors

Xinyu Bai^{1

2

3}, Grace H Attrill^{1

2

3}, Tuba N Gide^{1

2

3}, Peter M Ferguson^{1

2

4

5}, Kazi J Nahar^{1

2

3}, Ping Shang^{1

2

3}, Ismael A Vergara^{1

2

3}, Umaimainthan Palendira^{1

2

3

6}, Ines Pires da Silva^{1

2

3

7}, Matteo S Carlino^{1

7}, Alexander M Menzies^{1

2

8

9}, Georgina V Long^#^{1

2

3

8

9}, Richard A Scolyer^#^{1

2

3

4

5}, James S Wilmott^#^{1

2

3}, Camelia Quek^#^{10

11

12}

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.
² Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
³ Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
⁴ Royal Prince Alfred Hospital, Sydney, NSW, Australia.
⁵ NSW Health Pathology, Sydney, NSW, Australia.
⁶ Centenary Institute, The University of Sydney, Sydney, NSW, Australia.
⁷ Westmead and Blacktown Hospitals, Sydney, NSW, Australia.
⁸ Royal North Shore Hospital, Sydney, NSW, Australia.
⁹ Mater Hospital, North Sydney, NSW, Australia.
¹⁰ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. camelia.quek@melanoma.org.au.
¹¹ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. camelia.quek@melanoma.org.au.
¹² Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. camelia.quek@melanoma.org.au.

^# Contributed equally.

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 SIL^high subtype was enriched in regulatory T cells in the peritumoral space and showed upregulated expression of immune checkpoint molecules, while the SIL^low 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.

MeSH terms

Adolescent
Aged
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Immune Checkpoint Proteins
Immunotherapy
Melanoma* / therapy
T-Lymphocytes, Regulatory
Tumor Microenvironment
Young Adult

Substances

Immune Checkpoint Inhibitors
Immune Checkpoint Proteins

Grants and funding

ECF1153/Cancer Institute NSW (Cancer Institute New South Wales)