MCSP+ 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 Braun, Florian Weber, Katja Evert, Alexander Rochwarger, Christian M. Schürch, Katharina Limm, Peter J. Oefner, Reinhard Rachel, Felix Baumann, Jens Warfsmann, Lisa Schmidleithner, Kathrin Guetter, Parvaneh Mohammadi, Anja Ulmer, Sebastian Haferkamp, Christoph A. Klein, Melanie Werner‐Klein
Abstract
Abstract To investigate the early, poorly understood events driving metastatic progression, we searched for the earliest detectable disseminated cancer cells (DCCs), also often referred to as disseminated tumor cells (DTCs), in sentinel lymph node (SLN) biopsies of 492 patients with stage I–III melanoma. Using micromanipulator-assisted isolation of rare DCCs, single-cell mRNA and DNA sequencing, codetection by indexing immunofluorescence imaging and survival analysis, we identified melanoma-associated chondroitin sulfate proteoglycan (MCSP) + melanoma cells as metastasis founder cells (MFCs). We found that DCCs entering SLNs predominantly exhibited a transitory phenotype that, upon interferon-γ exposure triggered by CD8 T cells, dedifferentiated into a neural-crest-like phenotype. This was accompanied by increased production of small extracellular vesicles (sEVs) carrying the immunomodulatory proteins CD155 and CD276 but rarely programmed cell death protein 1 ligand 1. The sEVs suppressed CD8 T cell proliferation and function, facilitating colony formation. Targeting MCSP + MFCs or their immune escape mechanisms could be key to curing melanoma early by preventing manifestation of metastasis.