Metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization

Severin Guetter; Courtney König; 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 C. Braun; Florian Weber; Katja Evert; Alexander Rochwarger; Christian M. Schürch; Katharina Limm; Peter Josef Oefner; Reinhard Rachel; Felix Baumann; Jens Warfsmann; Lisa Schmidleithner; Kathrin Guetter; Parvaneh Mohammadi; Anja Ulmer

doi:10.1038/s43018-025-00963-w

Cancer BiologyNature CancerMay 16, 2025

Peer-reviewed journal article

Metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization

Severin Guetter iD, Courtney König, Huiqin Koerkel-Qu, Aleksandra Markiewicz iD, Sebastian Scheitler, Marie Katzer iD, Mark Berneburg iD, Philipp Renner iD, Beatrix Cucuruz iD, Leonhard Guttenberger, Veronika Naimer, Kathrin Weidele iD, Steffi Treitschke iD, Christian Werno iD, Hanna Jaser, Tonia Bargmann iD, Armin C. Braun iD, Florian Weber iD, Katja Evert iD, Alexander Rochwarger iD, Christian M. Schürch iD, Katharina Limm iD, Peter Josef Oefner iD, Reinhard Rachel iD, Felix Baumann iD, , Melanie Werner‐Klein iD

Abstract

The earliest steps of lethal metastasis in patients are incompletely understood. To dissect them, we prospectively searched for the earliest detectable disseminated cancer cells (DCC) in sentinel lymph node biopsies of 492 stage I-III patients. By visually-controlled, micromanipulator-assisted isolation and single cell transcriptome analysis of these extremely rare DCC, we identified MCSP+ melanoma cells as strong candidates for metastasis founder cells (MFC) 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. During transition from single cells to metastasis-initiating clusters, melanoma DCC were exposed to CD8 T cell attack, 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 exhibited an immunosuppressive activity on CD8 T cells. Our data indicate that either direct targeting of MFC employing MCSP or their immune escape mechanisms might be key for cure of early-stage melanoma.

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