![]() ![]() 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). 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.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |