CYSLTR1 rs320995 (T927C) and GSDMB rs7216389 (G1199A) Gene Polymorphisms in Asthma and Allergic Rhinitis: A Proof-of-Concept Study.

Background and Objective: Asthma and allergic rhinitis have been reported to be strongly associated with genetic factors. The aim of this study was to evaluate the accuracy of the TaqMan-MGB (minor groove binder) qPCR method for detecting CYSLTR1 rs320995 (T927C) and GSDMB rs7216389 (G1199A) gene polymorphisms as well as to explore the association of CYSLTR1 rs320995 and GSDMB rs7216389 polymorphisms with genetic susceptibility of Chinese patients with asthma and allergic rhinitis. Methods: In this study, 310 asthmatic patients and 60 healthy individuals were recruited in Peking Union Medical College Hospital. The CYSLTR1 rs320995 (T927C) and GSDMB rs7216389 (G1199A) gene polymorphisms in each group were analyzed by TaqMan-MGB qPCR and DNA sequencing which was regarded as the gold standard. After the validation of this method, additional 71 patients with allergic rhinitis and 72 patients with asthma combined with allergic rhinitis were selected and tested by using TaqMan-MGB qPCR. Results: The TaqMan-MGB qPCR results were fully consistent with DNA sequencing results (Kappa = 1, P<0.001). In addition, the results of the TaqMan-MGB qPCR assay were not affected by bilirubin and lipids. We found differential distribution of CYSLTR1 rs320995 genotypes in female patients with asthma combined with allergic rhinitis (χ 2=6.172, P=0.046, statistical power = 0.591). Specifically, the TT genotype is more frequent in women suffering from asthma with allergic rhinitis, whereas the TC genotype is more prevalent in healthy women. However, no such associations were observed in the GSDMB rs7216389 polymorphism. Conclusion: We have established a reliable TaqMan-MGB qPCR method for the detection of CYSLTR1 rs320995 and GSDMB rs7216389 polymorphisms. Moreover, the CYSLTR1 rs320995 polymorphism may be associated with genetic susceptibility of Chinese female patients with asthma and allergic rhinitis. Multicenter studies with larger sample sizes are required in the future.

Tumor immunological phenotype signature-based high-throughput screening for the discovery of combination immunotherapy compounds.

Combination immunotherapy is promising to overcome the limited objective response rates of immune checkpoint blockade (ICB) therapy. Here, a tumor immunological phenotype (TIP) gene signature and high-throughput sequencing-based high-throughput screening (HTS2) were combined to identify combination immunotherapy compounds. We firstly defined a TIP gene signature distinguishing "cold" tumors from "hot" tumors. After screening thousands of compounds, we identified that aurora kinase inhibitors (AKIs) could reprogram the expression pattern of TIP genes in triple-negative breast cancer (TNBC) cells. AKIs treatments up-regulate expression of chemokine genes CXCL10 and CXCL11 through inhibiting aurora kinase A (AURKA)-signal transducer and activator of transcription 3 (STAT3) signaling pathway, which promotes effective T cells infiltrating into tumor microenvironment and improves anti-programmed cell death 1 (PD-1) efficacy in preclinical models. Our study established a novel strategy to discover combination immunotherapy compounds and suggested the therapeutic potential of combining AKIs with ICB for the treatment of TNBC.