Mutations in BRCA-1 result in the functional loss of NKT cells (101.18)

Abstract

Abstract Natural killer T (NKT) cells have been shown to be important in regulating immune responses to tumors; however, the number and function of NKT cells are reduced in cancer patients. Genetic factors regulating NKT cell number and function have yet to be determined. The Breast Cancer Susceptibility gene 1 (BRCA-1) encodes a tumor suppressor gene that functions, in part, as a caretaker gene in preserving chromosomal stability. In this study we have investigated the role of BRCA-1 on NKT expression and function using a transgenic mouse model in which BRCA-1 is mutated. This mouse model has a direct translational link to a specific type of human breast cancer, because it develops the same genetic changes that are described in BRCA-1-related human cancer. BRCA-1 is highly expressed in the T cell lineages, and we have found that our NKT cell lines express BRCA-1 protein. When we examined the liver and spleens of BRCA-1 mutant mice, we found that the NKT cell population was significantly reduced, compared to wildtype control mice. The classical CD4 and CD8 T cell subpopulations were comparable between the BRCA-1 mutant mice and wildtype controls, which suggests that NKT cell population is specifically regulated BRCA-1. Collectively, our data suggest that determining whether genetic susceptibility alters the function of NKT cells, a key regulator of anti-tumor immune responses, could help in designing novel therapeutics targeting aggressive breast cancers.