Oral Presentation Australasian Society for Dermatology Research Annual Scientific Meeting 2024

Proteomic profiling of the tumour microenvironment and immune infiltrate of naevi and early melanoma shows the failure of the immune system in invasive melanoma. (#31)

Rachel Teh 1 2 3 , Ali Azimi 1 2 3 , Andy Tran 4 , John Ormerod 4 , Marina Ali 3 , Graham J Mann 2 5 , Jean Yang 4 , Pablo Fernández-Peñas 1 2 3
  1. The Department of Dermatology, Westmead Hospital, The University of Sydney, Westmead, NSW, Australia
  2. Centre for Cancer Research, Westmead Institute of Medical Research, The University of Sydney, Westmead, NSW, Australia
  3. Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
  4. School of Mathematics and Statistics, Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
  5. The John Curtin School of Medicial Research, College of Health and Medicine, Australian National University, Canberra, ACT, Australia

Background: In the microenvironment of melanocytic lesions, a multitude of mechanisms occur to maintain homeostasis. However, these mechanisms can be commandeered by tumour cells in favour of their proliferation and invasion. Studies investigating the role of the tumour microenvironment (TME) and immune system in melanocytic naevi is limited. This study investigated the dermis of Formalin-Fixed Paraffin-Embedded (FFPE) samples of melanocytic lesions to uncover TME and immune infiltrate proteins involved in melanoma progression.

Method: FFPE samples of non-chronic sun-exposed Normal Skin (NS) (n=12), Benign Naevi (n=16), Dysplastic Naevi (n=16), Melanoma in situ S (n=20) and Melanoma Minimally Invasive <1 mm Breslow thickness (n=21) were retrieved. Samples were sectioned, and dermis was captured by laser capture microdissection and macrodissection. Samples’ proteome was analysed using a data-independent acquisition mass spectrometry. Resultant spectra were searched against a T cell spectral library. Linear Models for Microarray Data identified dysregulated proteins. Enrichment and bioinformatics analysis of significant (p<0.05) differentially abundant proteins was performed using the online tools EnrichR and Ingenuity Pathway Analysis (IPA).

Results: A total of 1425 proteins were identified across the 85 samples. Gene Ontology Biological and Reactome enrichment analysis matched the identified proteins to immune and oncogenic processes such as regulation of phagocytosis, vasculature development, dendritic cell differentiation, neutrophile degranulation, and T cell mediated immune response to tumour cells. IPA bioinformatic analysis predicted an increase in the activity of immune processes such as quantity of antigen presenting cells and cellular infiltration of lymphocytes in DN and MIS lesions with a return to baseline activity in the MMI samples.   

Conclusion: In summary, this study reveals proteo-immune associations suggesting the immune system’s eventual failure leads to the progression of early melanoma. Further study into the TME and immune mechanisms that start to favour malignancy could help provide targets to prevent tumour progression.