Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer.

In recent years, homologous recombination deficiency (HRD) has not achieved the expected substantial promotion of immunotherapeutic efficacy in ovarian cancer. This study aims to explore the role of HRD functional phenotype as a powerful biomarker in identifying HRD patients who may benefit from immunotherapy. HRD functional phenotype, namely HRD-EXCUTE, was defined as the average level of the 15 hub genes upregulated in HRD ovarian cancer. A decision tree was plotted to evaluate the critical role of HRD-EXCUTE in HRD patients. Agents inducing HRD-EXCUTE were identified by CMAP web (Connectivity Map). The mechanisms and immunotherapeutic effect of PARPi and HDACi in promoting HRD-EXCUTE was examined in vitro and in vivo. The decision tree plotted on the basis of HRD and HRD-EXCUTE indicated the HRD patients without the HRD functional phenotype were largely unresponsive to immunotherapy, which was validated by the immunotherapeutic cohorts. Furthermore, loss of HRD-EXCUTE in the HRD patients attenuated immunogenicity and inhibited immune cells in tumor microenvironment. Moreover, Niraparib combined with Entinostat induced HRD-EXCUTE by activating the cGAS-STING pathway and increasing the histone acetylation. The combination therapy could enhance the cytotoxicity of immune cells, and promote pro-immune cells infiltrating into ascites, resulting in inhibited ovarian cancer growth. The HRD functional phenotype HRD-EXCUTE was set up as a potent biomarker to identify whether HRD patients can benefit from immunotherapy. Loss of HRD-EXCUTE in HRD patients were largely insensitive to immunotherapy. The combination of PARPi with HDACi could improve the efficacy of the PARPi-based immunotherapy in ovarian cancer by augmenting the HRD functional phenotype.

HHLA2 predicts improved prognosis of anti-PD-1/PD-L1 immunotherapy in patients with melanoma.

Background: As a recognized highly immunogenic tumor, immune checkpoint blockades (ICB) have been widely used as a systemic treatment option for melanoma. However, only about half of treated patients could benefit from it in Caucasians, and only about 15% in Chinese melanoma patients. Robust predictive biomarkers are needed. HHLA2, a new-found member of B7 family, is generally expressed in kinds of tumors, such as melanoma. This study focuses on illustrating the prognostic value of HHLA2 in melanoma immunotherapy and its association with tumor-infiltrating lymphocytes. Methods: HHLA2 expression in pan-cancer and the association with prognosis and immune microenvironment were identified by analyzing gene expression profiles from TCGA database with selected bioinformatics tools and methods. Tumor tissues from 81 cases with advanced and unresectable melanoma were collected for detecting HHLA2 and CD8 levels by immunohistochemistry. Results: HHLA2 was found to be ubiquitously expressed in pan-cancer with high level and correlate with the prognosis of patients. Further comprehensive analysis from TCGA database demonstrated that the highly expressed HHLA2 was remarkably correlated with better prognosis, high infiltration status of various immune-active cells and immune activated pathways in skin cutaneous melanoma (SKCM). Moreover, immunohistochemistry (IHC) analyses of FFPE tissue from melanoma patients revealed that HHLA2 high expression was strongly related to improved response to ICB and indicated a longer progression-free survival (PFS) and overall survival (OS). Besides, HHLA2 expression was found to have a positive association with the density of CD8+ TILs. Conclusion: Our findings revealed that high expression of HHLA2 has important values in predicting the response to ICB and indicating improved PFS and OS in patients with advanced and unresectable melanoma, suggesting that HHLA2 may serve as a costimulatory ligand in melanoma, which renders it as an ideal biomarker for immunotherapy.

Quality changes of clinical practice guidelines for respiratory diseases in China: A systematic review.

BACKGROUND: After the low quality of Chinese clinical practice guidelines (CPGs) for respiratory diseases published from 1979 to 2013 was reported, some handbooks were published to standardize guidelines' development recently. There was a great increase in the production and dissemination of CPGs annually in China, whose quality and potential impact were unknown. METHODS: A systematic search of four literature databases was performed for the period January 2013 to December 2018 to identify Chinese CPGs for respiratory diseases. Eligible CPGs were evaluated using the appraisal of guidelines for research and evaluation II (AGREE II) instrument. RESULTS: A total of 197 CPGs were identified for review. Compared with the result of previous study, the increased scores of the six AGREE II domains were screened: Scope and purpose (57.3% vs. 57.8%), Stakeholder involvement (17.6% vs. 25.0%), Rigor of development (10.2% vs. 13.2%), Clarity and presentation (55.2% vs. 58.4%), Applicability (9.3% vs. 25.9%), and Editorial independence (1.1% vs. 6.3%). The improved overall assessment for included CPGs were: Recommended (4, 2.0% vs. 0, 0%) and Recommended with modifications (26, 13.2% vs. 3, 2.8%). The improved level of evidence used to make recommendations were 59, 11.9% versus 168, 22.4% and 88, 17.7% versus 195, 26.0%, A and B, respectively. CONCLUSIONS: The overall quality of CPGs for respiratory diseases published from 2013 to 2018 in China was slightly improved, but had a big gap with the optimum level, especially in Rigor of development and Editorial independence. Increased efforts are required to enable the development of high-quality evidence-based CPGs for respiratory diseases.