FFAR2 expressing myeloid-derived suppressor cells drive cancer immunoevasion.

BACKGROUND: Emerging evidences suggest that aberrant metabolites contributes to the immunosuppressive microenvironment that leads to cancer immune evasion. Among tumor immunosuppressive cells, myeloid-derived suppressor cells (MDSCs) are pathologically activated and extremely immunosuppressive, which are closely associated with poor clinical outcomes of cancer patients. However, the correlation between MDSCs mediated immunosuppression and particular cancer metabolism remained elusive. METHODS: Spontaneous lung adenocarcinoma and subcutaneous mouse tumor models, gas chromatography-mass spectrometry (GC-MS) and immunofluorescence assay of patient-derived lung adenocarcinoma tissues, and flow cytometry, RNA sequencing and Western blotting of immune cells, were utilized. RESULTS: Metabolite profiling revealed a significant accumulation of acetic acids in tumor tissues from both patients and mouse model, which contribute to immune suppression and cancer progression significantly through free fatty acid receptor 2 (FFAR2). Furthermore, FFAR2 is highly expressed in the myeloid-derived suppressor cells (MDSCs) from the tumor of lung adenocarcinoma (LUAD) patients which is greatly associated with poor prognosis. Surprisingly, whole or myeloid Ffar2 gene deletion markedly inhibited urethane-induced lung carcinogenesis and syngeneic tumor growth with reduced MDSCs and increased CD8+ T cell infiltration. Mechanistically, FFAR2 deficiency in MDSCs significantly reduced the expression of Arg1 through Gαq/Calcium/PPAR-γ axis, which eliminated T cell dysfunction through relieving L-Arginine consumption in tumor microenvironment. Therefore, replenishment of L-Arginine or inhibition to PPAR-γ restored acetic acids/FFAR2 mediated suppression to T cells significantly. Finally, FFAR2 inhibition overcame resistance to immune checkpoint blockade through enhancing the recruitment and cytotoxicity of tumor-infiltrating T cells. CONCLUSION: Altogether, our results demonstrate that the acetic acids/FFAR2 axis enhances MDSCs mediated immunosuppression through Gαq/calcium/PPAR-γ/Arg1 signaling pathway, thus contributing to cancer progression. Therefore, FFAR2 may serve as a potential new target to eliminate pathologically activated MDSCs and reverse immunosuppressive tumor microenvironment, which has great potential in improving clinical outcomes of cancer immunotherapy.

Associations of social jetlag and emotional and behavioral problems among Chinese preschoolers.

To describe the prevalence of social jetlag among preschoolers and explore its association with emotional and behavioral problems, we conducted a cross-sectional survey of healthy development among preschool children in 11 cities in October and November 2017. The study included 27 200 children aged 3-6 years and the questionnaires were completed exclusively by their parents or main caregivers. Social jetlag was calculated by difference of sleep midpoint between weekdays and weekends. Emotional and behavioral problems (emotional symptoms, conduct problems, hyperactivity, peer interaction, and prosocial behavior) among preschoolers were assessed by the Strengths and Difficulties Questionnaire (SDQ). The binary logistic regression model was used to examine the association between social jetlag and emotional/behavioral problems in preschool children. The social jetlag was 0.60 hours in boys and 0.64 hours in girls. After adjusting for confounding factors as children' s gender, age, only child, living area, family economic status, mother's age and education, father's education, screen time and full-day sleep time, we found that longer social jetlag (≥1 h/d) was positively associated with overall emotional and behavioral problems (OR = 1.20, 95%CI: 1.10-1.32; P < .001), emotional symptoms (OR = 1.23, 95% CI: 1.11-1.15, P < .001), hyperactivity (OR = 1.20, 95%CI: 1.11-1.30, P < .001) and conduct problems (OR = 1.18, 95%CI: 1.07-1.31, P < .01). We found that social jetlag is prevalent among Chinese preschool children and is positively associated with emotional and behavioral problems.

Paper-based netlike rolling circle amplification (NRCA) for ultrasensitive and visual detection of SARS-CoV-2.

COVID-19 is a highly diffuse respiratory infection caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Currently, quantitative real-time polymerase chain reaction (qRT-PCR) technology is commonly used in clinical diagnosis of COVID-19. However, this method is time-consuming and labor-intensive, which is limited in clinical application. Here, we propose a new method for the ultrasensitive and visual detection of SARS-CoV-2 viral nucleic acid. The assay integrates with a paper device and highly efficient isothermal amplification technology - Netlike rolling circle amplification (NRCA), which can reach a limit of detection of 4.12 aM. The paper-based NRCA owns advantages of specificity, portability, visualization and low-cost. Therefore, this method can effectively meet the requirements of point-of-care testing, providing a novel molecular detection technology for clinical diagnosis of COVID-19 and promoting the development of NRCA devices.