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Background: Circular RNAs (circRNAs) are a special class of noncoding RNAs that are involved in gene regulation and compete with mRNA for miRNA binding sites. The roles of circRNAs in cancer, especially breast cancer (BC), are poorly understood. Materials and Methods: The expression levels of circRNA 0001073 (circ-1073) in BC cells (BCCs) and tissues and peritumoural tissues were detected by real-time quantitative reverse transcription-polymerase chain reaction. Kaplan-Meier analysis and receiver operating characteristic curves were used to evaluate relapse-free survival (RFS) and the diagnostic value of circ-1073 for BC, respectively. The biological functions of circ-1073 were determined by cell counting kit-8 assays, colony formation assays, flow cytometry, wound-healing assays, transwell assays, and xenograft model studies. RNA immunoprecipitation assays were conducted to identify the connection between circ-1073 and human antigen R (HuR). Results: Low circ-1073 expression was discovered in BCCs and BC tissues compared with normal mammary epithelial cells and peritumoural tissues, respectively. Circ-1073 downregulation was significantly associated with an unfavourable prognosis, including a shorter RFS, in BC patients. Circ-1073 is a valuable diagnostic biomarker for BC. Circ-1073 overexpression significantly inhibited BCC proliferation and induced apoptosis by increasing Cleaved Caspase-3/9 levels. Moreover, circ-1073 upregulation significantly suppressed cell mobility and epithelial-mesenchymal transition. Notably, xenograft tumour growth was inhibited by the intratumoural injection of nanoparticles containing the circ-1073 plasmid or by circ-1073 overexpression, and this inhibition was accompanied by HuR upregulation. Conclusion: Circ-1073 functions as a tumour suppressor in BC, suggesting its potential as a novel therapeutic target in BC.

The impairment of immunity characterized by T cell exhaustion is the main cause of death in patients with sepsis after the acute phase. Although PD-1 blockade is highly touted as a promising treatment for improving prognosis, the role of PD-1 plays in sepsis and particularly its different roles in different periods are still very limited. A recent study revealed LAG3 can resist the therapeutic effect of PD-1 blockade in tumor, which inspired us to understand their role in sepsis. We enrolled 26 patients with acute sepsis from 422 candidates using strict inclusion criteria. Follow-up analysis revealed that the expression levels of PD-1 were rapidly increased in the early stage of sepsis but did not change significantly as infection continued ( P < 0.05). However, the expression of LAG3 was contrary to that of PD-1. Compared with LAG3 or PD-1 single-positive T cells, T cells coexpressing LAG3 and PD-1 were significantly exhausted ( P < 0.05). The proportion of coexpressing T cells was negatively correlated with the total number of lymphocytes ( r = −0.653, P = 0.0003) and positively correlated with the SOFA score ( r = 0.712, P < 0.0001). In addition, the higher the proportion of coexpressing T cells was, the longer the hospital stay and the higher the mortality. These results showed that LAG3 and PD-1 had a potential synergistic effect in regulating the gradual exhaustion of T cells in sepsis, which seriously affected the clinical prognosis of patients. Therefore, LAG3 and PD-1 double-positive T cells are an important indicator for immunity detection and prognostic evaluation. In the future, precision therapy may pay more attention to the different expression patterns of these two molecules.

Background: Since T cell exclusion contributes to tumor immune evasion and immunotherapy resistance, how to improve T cell infiltration into solid tumors becomes an urgent challenge. Methods: We employed deep learning to profile the tumor immune microenvironment (TIME) in triple negative breast cancer (TNBC) samples from TCGA datasets and noticed that fibroblast growth factor receptor (FGFR) signaling pathways were enriched in the immune-excluded phenotype of TNBC. Erdafitinib, a selective FGFR inhibitor, was then used to investigate the effect of FGFR blockade on TIME landscape of TNBC syngeneic mouse models by flow cytometry, mass cytometry (CyTOF) and RNA sequencing. Cell Counting Kit-8 (CCK-8) assay and transwell migration assay were carried out to detect the effect of FGFR blockade on cell proliferation and migration, respectively. Cytokine array, western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) were employed to investigate the potential mechanism by which FGFR inhibition enhanced T cell infiltration. Results: Blocking FGFR pathway by Erdafitinib markedly suppressed tumor growth with increased T cell infiltration in immunocompetent mouse models of TNBC. Mechanistically, FGFR blockade inhibited cancer-associated fibroblasts (CAFs) proliferation, migration and secretion of vascular cell adhesion molecule 1 (VCAM-1) by down-regulating MAPK/ERK pathway in CAFs, thus promoting T cell infiltration by breaking physical and chemical barriers built by CAFs in TIME. Furthermore, we observed that FGFR inhibition combined with immune checkpoint blockade therapy (ICT) greatly improved the therapeutic response of TNBC tumor models. Conclusions: FGFR blockade enhanced ICT response by turning immune “cold” tumor into “hot” tumor, providing remarkable implications of FGFR inhibitors as adjuvant agents for combinatorial immunotherapy.

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