Mechanisms of tumor persistence in metastatic melanoma following successful immunotherapy

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. SIGNIFICANCEThis 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.