IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer.

BACKGROUND: PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear. METHODS: The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-γ signals was assessed. RESULTS: The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-γ receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-γ into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-γ injection (P=0.01). CONCLUSIONS: Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-γ status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.

Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes.

Ovarian clear cell carcinoma (OCCC) shows unique clinical features including an association with endometriosis and poor prognosis. We previously reported that the contents of endometriotic cysts, especially high concentrations of free iron, are a possible cause of OCCC carcinogenesis through iron-induced persistent oxidative stress. In this study, we conducted gene expression microarray analysis using 38 ovarian cancer cell lines and identified genes commonly expressed in both OCCC cell lines and clinical samples, which comprise an OCCC gene signature. The OCCC signature reproducibly predicts OCCC specimens in other microarray data sets, suggesting that this gene profile reflects the inherent biological characteristics of OCCC. The OCCC signature contains known markers of OCCC, such as hepatocyte nuclear factor-1beta (HNF-1beta) and versican (VCAN), and other genes that reflect oxidative stress. Expression of OCCC signature genes was induced by treatment of immortalized ovarian surface epithelial cells with the contents of endometriotic cysts, indicating that the OCCC signature is largely dependent on the tumor microenvironment. Induction of OCCC signature genes is at least in part epigenetically regulated, as we found hypomethylation of HNF-1beta and VCAN in OCCC cell lines. This genome-wide study indicates that the tumor microenvironment induces specific gene expression profiles that contribute to the development of distinct cancer subtypes.

Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors.

The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations such as pregnancy, termination of pregnancy, miscarriage, and adoption, as well as less common scenarios such as pregnancies conceived through assisted reproductive technologies. The Pedigree Standardization Task Force (PSTF) was organized through the Professional Issues Committee of the National Society of Genetic Counselors, to establish recommendations for universal standards in human pedigree nomenclature. Nomenclature was chosen based on current usage, consistency among symbols, computer compatibility, and the adaptability of symbols to reflect the rapid technical advances in human genetics. Preliminary recommendations were presented for review at three national meetings of human genetic professionals and sent to > 100 human genetic professionals for review. On the basis of this review process, the recommendations of the PSTF for standardized human pedigree nomenclature are presented here. By incorporating these recommendations into medical genetics professional training programs, board examinations, genetic publications, and pedigree software, the adoption of uniform pedigree nomenclature can begin. Usage of standardized pedigree nomenclature will reduce the chances for incorrect interpretation of patient and family medical and genetic information. It may also improve the quality of patient care provided by genetic professionals and facilitate communication between researchers involved with genetic family studies.

Recommendations for standardized human pedigree nomenclature.

The construction of an accurate family pedigree is a fundamental component of a clinical genetic evaluation and of human genetic research. Previous surveys of genetic counselors and human genetic publications have demonstrated significant inconsistencies in the usage of common pedigree symbols representing situations such as pregnancy, termination of pregnancy, miscarriage, and adoption, as well as less common scenarios such as pregnancies conceived through assisted reproductive technologies. The Pedigree Standardization Task Force (PSTF) was organized through the Professional Issues Committee of the National Society of Genetic Counselors, to establish recommendations for universal standards in human pedigree nomenclature. Nomenclature was chosen based on current usage, consistency among symbols, computer compatibility, and the adaptability of symbols to reflect the rapid technical advances in human genetics. Preliminary recommendations were presented for review at three national meetings of human genetic professionals and sent to >100 human genetic professionals for review. On the basis of this review process, the recommendations of the PSTF for standardized human pedigree nomenclature are presented here. By incorporating these recommendations into medical genetics professional training programs, board examinations, genetic publications, and pedigree software, the adoption of uniform pedigree nomenclature can begin. Usage of standardized pedigree nomenclature will reduce the chances for incorrect interpretation of patient and family medical and genetic information. It may also improve the quality of patient care provided by genetic professionals and facilitate communication between researchers involved with genetic family studies.