Animals; Ataxia Telangiectasia Mutated Proteins; Cell Count; Cell Proliferation; Haploinsufficiency; Humans; Loss of Function Mutation; Macrophages; Melanoma; Mice; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Nevus; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Tumor Microenvironment
Melanomas accumulate a high burden of mutations that could potentially generate neoantigens, yet somehow suppress the immune response to facilitate continued growth. In this study, we identify a subset of human melanomas that have loss-of-function mutations in ATR, a kinase that recognizes and repairs UV-induced DNA damage and is required for cellular proliferation. ATR mutant tumors exhibit both the accumulation of multiple mutations and the altered expression of inflammatory genes, resulting in decreased T cell recruitment and increased recruitment of macrophages known to spur tumor invasion. Taken together, these studies identify a mechanism by which melanoma cells modulate the immune microenvironment to promote continued growth.
Chen, Chi-Fen; Ruiz-Vega, Rolando; Vasudeva, Priya; Espitia, Francisco; Krasieva, Tatiana B; de Feraudy, Sebastien; Tromberg, Bruce J; Huang, Sharon; Garner, Chad P; Wu, Jie; Hoon, Dave S B; and Ganesan, Anand K, "ATR Mutations Promote the Growth of Melanoma Tumors by Modulating the Immune Microenvironment." (2017). Articles, Abstracts, and Reports. 1606.