Abstract LB056: The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution

Abstract Cutaneous melanoma is a highly immunogenic malignancy, surgically curable at early stages, but life-threatening when metastatic. The spatial organization of the tumor ecosystem during early-stage melanoma is not well understood. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially-resolved micro-region transcriptomics to study immune evasion and immunoediting in primary melanoma. We collected highly multiplexed single-cell data from 70 distinct histological regions from 13 specimens (patients) selected to have multiple progression-associated histologies within a single resection. These histologies range from pre-malignant fields in which melanocytic atypia represents the first steps in cancer initiation to non-invasive (radial growth phase) and invasive (vertical growth phase) primary melanoma that eventually gives rise to disseminated disease. 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 primary invasive tumor. Hallmarks of immunosuppression were detectable as early as the melanoma precursor stage, and when tumors become locally invasive, a consolidated and spatially restricted environment with multiple overlapping immunosuppressive mechanisms forms along the tumor-stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1 and by PDL1-expressing macrophages and dendritic cells engaging activated T cells. However, only a few millimeters away, T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can co-exist within a few millimeters of each other in a single specimen. Multiplexed single-cell imaging and micro-region mRNA profiling link morphological and molecular features of tumor evolution within and across primary cancer specimens, revealing highly localized programs of immune and tumor cell communication via paracrine cytokine signaling and direct cell-cell contact. Citation Format: Ajit Johnson Nirmal, Zoltan Maliga, Tuulia Vallius, Brian Quattrochi, Alyce Chen, Connor Jacobson, Roxanne Pelletier, Clarence Yapp, Raquel Arias-Camison, Yu-An Chen, Christine Lian, George F. Murphy, Sandro Santagata, Peter K. Sorger. The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB056.