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#HARVARD FAS SOFTWARE DOWNLOAD ENDNOTE SKIN#However, while the removal of dysplastic nevi with higher grades of atypia is standard clinical practice ( 17), it is now thought that the majority of primary cutaneous melanomas are not derived from nevi, but rather arise de novo from fields of melanocytic atypia, particularly in sun-damaged skin ( 18, 19). The study of recurrent mutations found in cutaneous melanoma has yielded models of sequential tumor evolution starting with the formation of dysplastic nevi ( 4). Vertical growth phase melanomas can be endophytic or exophytic, corresponding to vertical growth down into the dermis or upward above the skin, at times resulting in polypoid lesions that erupt from the surrounding skin ( 16). However, invasive growth into the dermis is both expansile and highly mitotic, giving rise to vertical growth phase melanoma with a high potential for metastasis ( 15). MIS can spread within the epidermis and focally invade the superficial dermis without expansile growth, giving rise to radial growth phase melanoma, which has an excellent prognosis upon complete excision. These precursor fields can develop into melanoma in situ (MIS), a proliferation and confluence of malignant melanocytes within the epidermis but without invasion into the underlying dermis ( 14). Fields of melanocytic atypia, the earliest signs of oncogenic transformation, involve increases in melanocyte number and density, enlargement, and irregularity of melanocyte nuclei, movement of melanocytes away from the dermal–epidermal junction ( 12), and loss of 5-hydroxymethylcytosine (5hmC) epigenetic marks ( 5, 13). Normal skin is characterized by evenly spaced melanocytes, which are neural crest–derived melanin-producing cells ( 10) located between cuboidal basal keratinocytes on the apical face of the dermal–epidermal junction ( 11). It is diagnosed and staged using classic methods such as histopathologic assessment of hematoxylin and eosin (H&E)–stained formaldehyde-fixed, paraffin-embedded (FFPE) skin biopsies, complemented in some cases by IHC ( 9). Although treatment of metastatic melanoma has benefited from modern targeted therapies guided by genetic biomarkers (BRAF and MEK inhibitors) and by immune-checkpoint inhibitors, primary melanoma is treated surgically. #HARVARD FAS SOFTWARE DOWNLOAD ENDNOTE DRIVER#However, oncogenic transformation and immune escape remain only partly understood due in part to a high mutational burden in morphologically normal skin, estimated in Caucasians to be >100 driver mutations per cm 2 by late middle age ( 8). #HARVARD FAS SOFTWARE DOWNLOAD ENDNOTE DRIVERS#In the case of primary cutaneous melanoma, DNA sequencing has identified recurrent mutations in drivers such as BRAF, NRAS, PTEN, and TP53 ( 4–6), and dissociative single-cell RNA sequencing (scRNA-seq) has revealed progression-associated changes in immune cell states ( 7). The competition between editing by immune cells and escape by cancer cells generates a complex ecosystem whose molecular features and physical organization determine disease outcomes and responsiveness to therapy ( 2, 3). Tumorigenesis commonly involves a progressive failure of immune cells, particularly T cells, to detect cancer cells as they accumulate mutations promoting growth, invasion, and metastasis ( 1). ![]() Thus, invasion and immunoediting can coexist within a few millimeters of each other in a single specimen. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. 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. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor–stromal boundary. Hallmarks of immunosuppression are already detectable in precursor regions. ![]() 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. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. Cutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. ![]()
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