BackgroundNovel therapies are needed to treat recurrent and advanced cervical cancer (CC), as their prognosis remains very poor. Although therapies targeting the programmed cell death protein 1 (PD-1) pathway have been approved for CC, a large subset of patients exhibit innate resistance. Using checkpoint inhibitors in combination could enhance their efficacy.MethodsBlood samples, tumor specimens, and peritumorous (PT) tissues were obtained from patients with CC. The inhibitory receptor expression and phenotypical analysis of CD8+ T cells in CC specimens were analyzed by flow cytometry. The ligands of CD96 expressed by tumor cells were measured by immunohistochemistry and immunofluorescence. Sensitivity to pembrolizumab was evaluated by an ex vivo treatment assay based on the single-cell culture of CC specimens. The efficacies of PD-1 and/or CD96 blockades were explored using an ex vivo treatment assay and an human papillomavirus-positive TC-1 xenograft mouse model in vivo.ResultsWe found that CD96 expression was elevated on CD8+ tumor-infiltrating lymphocytes (TILs) from patients with CC who were insensitive to the PD-1 blockade. These CD96-expressing CD8+ TILs often coexpressed PD-1. The ratio of the CD96+CD8+/CD96−CD8+ T-cell gene signature from the scRNA-seq data was significantly associated with the poor survival of patients with cervical squamous cell carcinoma and endocervical adenocarcinoma. The costimulatory receptor CD226, which competes with CD96, was downregulated in tumors compared with blood and PT tissue. CD96 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) were upregulated on intratumoral CD8+ T cells. The CD226/CD96/TIGIT signaling ligands were widely expressed in CC tumor tissues. Phenotypical profiling showed that PD-1+CD96+CD8+ TILs exhibited a terminally exhausted effector phenotype with high levels of T-cell immunoglobulin mucin receptor 3 (TIM-3) and granzyme B (GZMB) and extremely low levels of proinflammatory cytokines and cytotoxic molecules. PD-1+CD96 cells exhibited a precursor exhausted phenotype with TCF-1 positivity. CD96 was further upregulated by CD8+ TILs on PD-1 blockade. Treatment with the CD96 blockade significantly enhanced the PD-1 blockade to blunt tumor growth and improve the function of CD8+ TILs in both mouse and CC specimen models.ConclusionsOur findings showed that CD96 and PD-1 cooperatively and negatively regulate the function of CD8+ TILs, and CD96 blockade has promise for use in combination with PD-1 blockade for the treatment of CC.
Aim:The interactions between plants and soil microbes play crucial roles in modulating the function and stability of terrestrial ecosystems. However, the relationships between plant and soil microbial diversity for different taxa have remained been elusive. Location: Northern China.Major taxa: Plant and soil microbes of grassland ecosystems. Time period: 2018 and 2019. Methods: We conducted a transect survey across grasslands to measure plant diversity, plant traits, and soil microbial diversity. High throughput sequencing was used to assess soil microbial diversity for bacterial 16S ribosomal RNA (16S) and fungal internal transcribed spacer (ITS) regions on an Illumina MiSeq. The random forest algorithm was used to determine the important spatial and environmental variables in predicting plant and microbial diversity, and structural equation modelling was used to examine the direct and indirect effects of climatic and edaphic variables on plant and microbial diversity.Results: Plant diversity was positively correlated with the diversity of soil fungi, particularly for predicted arbuscular mycorrhizal fungi (AMF) and saprotrophic fungi, and they were positively related to soil nutrients and texture. However, the correlation between plant and bacterial diversity varied by phyla and functional guilds, resulting in decoupling between plant and soil bacterial diversity. Community weighted mean leaf C:N ratio indirectly decreased soil fungal diversity through a negative relationship with soil total nitrogen. Soil bacterial and fungal diversity increased with increasing functional richness of specific leaf area and stem density, respectively.Main conclusions: These findings have contributed to unravelling the direct and indirect linkages between plant and soil fungal diversity, highlighting particularly strong linkages between plant diversity and predicted AMF and saprotrophic fungi diversity.However, we failed to detect an overall linkage between plant and soil bacterial diversity. Still, our findings suggest that integrating soil fungi into the framework of plant diversity conservation is conducive to biodiversity restoration in degraded grassland ecosystems.
Methods:We collected the clinical data of 260 patients admitted to the hospital from April 2003 to September 2019 with pathologically confirmed intravenous leiomyomatosis (IVL) and followed up with these patients regularly. Univariate and multivariate logistic regression analyses were carried out on the relevant recurrence factors. Results: A total of 166 patients were regularly followed up, the median follow-up time was 36 (range 2-168) months, 14 (5.4%) patients eventually relapsed, and the median recurrence time was 8.5 (range 2-42) months. The univariate analysis showed that age (p = 0.003) and surgical type (p < 0.001) were associated with recurrence, and multivariate regression analysis demonstrated that surgical type was the only factor associated with recurrence (p < 0.001, OR 20.01). Conclusions: The use of gonadotrophin releasing hormone agonist (GnRHa) cannot reduce the postsurgical recurrence rate of patients with UIVL. Compared to total hysterectomy and bilateral salpingo-oophorectomy (TH-BSO), total hysterectomy (TH) does not increase the odds of recurrence, but the chance of recurrence with tumorectomy (TE) is 20 times higher than that of TH-BSO.
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