CXCL14 Acts as a Specific Carrier of CpG DNA into Dendritic Cells and Activates Toll-like Receptor 9-mediated Adaptive Immunity

CXCL14 is a primordial chemokine that plays multiple roles in tumor suppression, autoimmune arthritis, and obesity-associated insulin resistance. However, the underlying molecular mechanisms are unclear. Here, we show that CXCL14 transports various types of CpG oligodeoxynucleotide (ODN) into the endosomes and lysosomes of bone marrow-derived dendritic cells (DCs), thereby activating Toll-like receptor 9 (TLR9). A combination of CpG ODN (ODN2395) plus CXCL14 induced robust production of IL-12 p40 by wild-type, but not Tlr9-knockout, DCs. Consistent with this, ODN2395-mediated activation of DCs was significantly attenuated in Cxcl14-knockout mice. CXCL14 bound CpG ODN with high affinity at pH 7.5, but not at pH 6.0, thereby enabling efficient delivery of CpG ODN to TLR9 in the endosome/lysosome. Furthermore, the CXCL14-CpG ODN complex specifically bound to high affinity CXCL14 receptors on DCs. Thus, CXCL14 serves as a specific carrier of CpG DNA to sensitize TLR9-mediated immunosurveillance

BRCA1/2 Mutation Frequency is HIGH in Japanese Triple-Negative Breast Cancer Patients

Germline mutations of BRCA1/2 genes cause hereditary breast and/or ovarian cancer. However, whether guidelines like those of the National Comprehensive Cancer Network (NCCN) can suitably predict the likelihood of BRCA1/2 mutations in the Japanese population is unclear. Methods BRCA1/2 gene mutation frequencies were investigated in relation to parameters such as age, family history (FH), and breast cancer subtype using data collected from 922 Japanese breast cancer patients who underwent surgery between September 2010 and June 2013. BRCA1/2 mutations were present in 15 of 57 (26.3%) tested patients. The frequency of the mutations was not significantly related to age. Among the 180 patients who reported an FH of breast cancer, 11 of the 37 who were tested (29.7%) were positive for BRCA1/2 mutations. Of those with an FH of ovarian cancer (n = 34), seven of 12 patients tested (58.3%) were carriers of BRCA1/2 (P = 0.013). Six of these seven carriers were triple-negative breast cancer (TNBC) patients. In all, there were 97 TNBC patients, and the presence of the BRCA1/2 mutation in this subgroup was significantly greater than in non-TNBC patients, with 12 of 17 TNBC patients (70.5%) testing positive (P = 0.03). There were 59 TNBC patients < 60 years of age, and of the 16 (27.1%) who underwent BRCA1/2 genetic testing, 11 (68.8%) were found to have mutations in BRCA1/2. Among the TNBC patients, 29 also reported an FH of breast or ovarian cancer; of these, nine of the 13 tested (69.2%) were positive for a BRCA1/2 mutation. The data demonstrate that BRCA1/2 mutations are observed more frequently in TNBC patients, especially those < 60 years of age or in combination with an FH of breast and/or ovarian cancer, suggesting that some of the NCCN guidelines can adequately predict BRCA1/2 carriers in the Japanese population

CXCL14 Acts as a Specific Carrier of CpG DNA into Dendritic Cells and Activates Toll-like Receptor 9-mediated Adaptive Immunity

CXCL14 is a primordial chemokine that plays multiple roles in tumor suppression, autoimmune arthritis, and obesity-associated insulin resistance. However, the underlying molecular mechanisms are unclear. Here, we show that CXCL14 transports various types of CpG oligodeoxynucleotide (ODN) into the endosomes and lysosomes of bone marrow-derived dendritic cells (DCs), thereby activating Toll-like receptor 9 (TLR9). A combination of CpG ODN (ODN2395) plus CXCL14 induced robust production of IL-12 p40 by wild-type, but not Tlr9-knockout, DCs. Consistent with this, ODN2395-mediated activation of DCs was significantly attenuated in Cxcl14-knockout mice. CXCL14 bound CpG ODN with high affinity at pH 7.5, but not at pH 6.0, thereby enabling efficient delivery of CpG ODN to TLR9 in the endosome/lysosome. Furthermore, the CXCL14-CpG ODN complex specifically bound to high affinity CXCL14 receptors on DCs. Thus, CXCL14 serves as a specific carrier of CpG DNA to sensitize TLR9-mediated immunosurveillance