The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution

TLDR

Cutaneous melanoma is highly immunogenic, curable early but lethal when metastatic, and its tumor ecosystem reorganization provides an ideal setting to study immunoediting and immune evasion. The study integrates high‑plex imaging, 3‑D microscopy, and spatial transcriptomics to investigate immune evasion and immunoediting in primary melanoma. The authors used high‑plex imaging, 3‑D microscopy, and spatial transcriptomics guided by histopathology to map cytokine gradients, MHC‑II/IDO1 expression, and PD1‑PDL1 cell contacts that drive tumor‑immune interactions. Neighborhoods of tumor, immune, and stromal cells shift along a progression axis, with early immunosuppression detectable in precursors, a localized suppressive microenvironment forming at the tumor‑stromal boundary during invasion, and cytotoxic T cells engaging melanoma cells a few millimeters away, illustrating coexistence of invasion and immunoediting. The article is highlighted in the In This Issue feature, p.

Abstract

Cutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor-stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1-PDL1-mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can coexist within a few millimeters of each other in a single specimen. The reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classic histopathology, spatial profiling of proteins and mRNA reveals recurrent morphologic and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell-cell contact. This article is highlighted in the In This Issue feature, p. 1397.