Spatial profiling of cutaneous melanoma at the single-cell level provided molecular features of progression and immunosuppression, which include paracrine cytokine signaling and direct immune cell-cell contact.,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
Group 2 innate lymphoid cells (ILC2) are essential to maintain tissue homeostasis.,In cancer, ILC2 can harbor both pro- and anti-tumorigenic functions but we know very little about their underlying mechanisms, nor whether they could be clinically relevant or targeted to improve patient outcomes.,Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis.,ILC2 are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) which coordinate the recruitment and activation of eosinophils to enhance anti-tumor responses.,Tumor-infiltrating ILC2 expressed programmed cell death protein-1 (PD-1), which limited their intratumoral accumulation, proliferation and anti-tumor effector functions.,This inhibition could be overcome in vivo by combining IL-33-driven ILC2 activation with PD-1 blockade to significantly increase anti-tumor responses.,Together, our results identified ILC2 as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for anti-tumor immunotherapies.