Mechanisms of tumor persistence in metastatic melanoma following successful immunotherapy

ABSTRACT Persistent stable lesions represent a common but ambiguous outcome in melanoma patients receiving immune checkpoint inhibitors (ICIs). However, these lesions are infrequently removed and poorly characterized. Here, we perform in-depth multi-omics spatial profiling on persistent stable lesions from six ICI-treated patients. In one, the proportion of viable and proliferating tumor cells was similar to that of site-matched tumors from patients progressing during ICI. Extensive infiltration with cytotoxic T cells and a high level of programmed cell death were also observed. Some quiescent cancer cells were present, but this was not the dominant tumor state. A second stable lesion, while pathologically negative, also contained proliferative tumor nests with proximate immune cells. These findings provide evidence in patients for extended tumor mass dormancy in which cell death balances ongoing proliferation and further demonstrate that persistent stable lesions can be reservoirs of viable tumor cells with implications for clinical monitoring and management. SIGNIFICANCE This study demonstrates that, following immunotherapy, persistent stable melanomas can arise through tumor mass dormancy rather than quiescence. Mass dormancy is characterized by active tumor cell proliferation and compensatory programmed cell death. Thus, viable tumor cells in some stable lesions have the potential to reactivate disease should ongoing immunosurveillance fail. Competing Interest Statement P.K.S. is a cofounder and member of the Board of Directors of Glencoe Software and a member of the Scientific Advisory Board for RareCyte and Montai Health; he holds equity in Glencoe and RareCyte. P.K.S. is a consultant for Merck. E.V.A is consulting for Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Serinus Bio, and TracerBio, hold equity in Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, Serinus Bio, Syapse, and TracerDx; editorial board in Science Advances; received funding from Novartis, BMS, Sanofi, NextPoint. EB serves as a consultant/advisory board member for Pfizer, Immunocore, Obsidian, Zola, Anaveon, Merck and Werewolf pharmaceuticals. Clinical trial support from Genentech. D.L. has received travel expenses and speech honorariums from Genentech. The above authors declare that none of these relationships have influenced the content of this manuscript, and the other authors declare no competing interests.