Abstract 5530: Metastasis founder cells activate immunsuppression early in human metastatic colonization

Abstract Metastatic dissemination occurs very early in melanoma, often before diagnosis, rendering prevention of metastasis formation an important therapeutic goal. However, the earliest steps of lethal metastasis in patients are incompletely understood. Therefore, in this study we searched for the earliest detectable disseminated cancer cells (DCC) in sentinel lymph node biopsies of 492 stage I-III melanoma patients. We used micromanipulator-assisted isolation and single-cell transcriptome analysis of these extremely rare DCC and identified melanoma -associated chondroitin sulfate proteoglycan (MCSP) expressing melanoma cells as strong candidates for metastasis founder cells in lymph nodes. Based on a median follow-up time of 6 years, their detection was the strongest predictor of systemic metastasis and death upon multivariable analysis. Single-cell transcriptome analysis revealed that melanoma DCC were exposed to CD8 T cell attack during the transition from single cells to metastasis-initiating clusters, activated the extracellular vesicular exosomal pathway, and expressed the immunomodulatory proteins CD155 and CD276, but rarely PD-L1. CD155- and CD276-positive extracellular vesicles from patient-derived DCC models showed an immunosuppressive activity on CD8 T cells. In conclusion, our data suggest that either direct targeting of metastasis-founder cell with MCSP or their immune escape mechanisms may be key to curing early-stage melanoma. Citation Format: Severin Guetter, Courtney Koenig, Huiqin Koerkel-Qu, Aleksandra Markiewicz, Sebastian Scheitler, Marie Katzer, Mark Berneburg, Philipp Renner, Beatrix Cucuruz, Leonhard Guttenberger, Veronika Naimer, Kathrin Weidele, Steffi Treitschke, Christian Werno, Hanna Jaser, Tonia Bargmann, Armin Braun, Florian Weber, Katharina Limm, Reinhard Rachel, Felix Baumann, Lisa Schmidleithner, Kathrin Schambeck, Anja Ulmer, Sebastian Haferkamp, Christoph Klein, Melanie Werner-Klein. Metastasis founder cells activate immunsuppression early in human metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5530.