Poster Presentation 37th Lorne Cancer Conference 2025

The Cellular Landscape of In-Transit Melanoma and Resistance to Immune Checkpoint Blockade (#105)

Louise Baldwin 1 2 , Ghamdan Al-Eryani 1 2 3 , Sonny Ramkomuth 1 , Camelia Yu-Jing Quek 4 5 6 , John Reeves 1 , Kate Harvey 1 , Georgina Long 4 5 6 7 , Richard Scolyer 4 5 6 8 , Alex Swarbrick 1 2
  1. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, Faculty of Medicine UNSW Sydney, Darlinghurst, NSW, Australia
  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA
  4. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
  5. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
  6. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  7. Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia
  8. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital & NSW Health Pathology, Sydney, NSW, Australia

The development of in transit metastases of melanoma (ITM) presents a unique clinical challenge given the potential of these metastatic lesions to disseminate and their propensity to recur. While immune checkpoint blockade (ICB) therapies have improved outcomes, half of patients treated will have resistant disease and little is known about the mechanisms, particularly within the setting of ITM disease.  ITM disease offers a unique clinical and cellular landscape to study the underlying biology of ITM and the influence of ICB on disease progression. Here, we apply single cell multiomics on ITM biopsies from patients that received anti-PD-1 monotherapy or combination anti-PD-1+CTLA-4 therapies. We find a cellular landscape dominated by melanocytes with limited immune and stromal cell infiltration. We observed that genetic diversity and dedifferentiation within the melanocyte compartment associated with ICB resistance and disease progression. Conversely, T cell clonal expansion and clone sharing among specific tissue-resident memory T cell subsets were associated with ICB response. Our results provide the first multiomic cellular examination of ITM in the context of ICB and reinforce the importance of genomic and cellular heterogeneity in ICB response, resistance, and disease progression. These insights may inform the development of novel therapeutic strategies to overcome ICB resistance and improve outcomes for patients with ITM disease.