ATR Mutations Promote the Growth of Melanoma Tumors by Modulating the Immune Microenvironment.

Publication Title

Cell Rep

Authors

Chi-Fen Chen
Rolando Ruiz-Vega
Priya Vasudeva
Francisco Espitia
Tatiana B Krasieva
Sebastien de Feraudy
Bruce J Tromberg
Sharon Huang, Department of Molecular Oncology, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center, Santa Monica, CA 90404
Chad P Garner
Jie Wu
Dave S B Hoon, Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Pacific Neuroscience Institute, Saint John's Health Center, Providence Health Systems, Santa Monica, CA, 90404, USAFollow
Anand K Ganesan

Document Type

Article

Publication Date

3-7-2017

Keywords

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

Abstract

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.

Clinical Institute

Cancer

Specialty/Research Institute

Oncology

Specialty/Research Institute

Dermatology