Landscape of adenosine pathway and immune checkpoint dual blockade in NSCLC: progress in basic research and clinical application.

Lung cancer poses a global threat to human health, while common cancer treatments (chemotherapy and targeted therapies) have limited efficacy. Immunotherapy offers hope of sustained remission for many patients with lung cancer, but a significant proportion of patients fail to respond to treatment owing to immune resistance. There is extensive evidence to suggest the immunosuppressive microenvironment as the cause of this treatment failure. Numerous studies have suggested that the adenosine (ADO) pathway plays an important role in the formation of an immunosuppressive microenvironment and may be a key factor in the development of immune resistance in EGFR-mutant cell lung cancer. Inhibition of this pathway may therefore be a potential target to achieve effective reversal of ADO pathway-mediated immune resistance. Recently, an increasing number of clinical trials have begun to address the broad prospects of using the ADO pathway as an immunotherapeutic strategy. However, few researchers have summarized the theoretical basis and clinical rationale of the ADO pathway and immune checkpoint dual blockade in a systematic and detailed manner, particularly in lung cancer. As such, a timely review of the potential value of the ADO pathway in combination with immunotherapy strategies for lung cancer is warranted. This comprehensive review first describes the role of ADO in the formation of a lung tumor-induced immunosuppressive microenvironment, discusses the key mechanisms of ADO inhibitors in reversing lung immunosuppression, and highlights recent evidence from preclinical and clinical studies of ADO inhibitors combined with immune checkpoint blockers to improve the lung cancer immunosuppressive microenvironment.

Ferroptosis in cancer immunity and immunotherapy: Multifaceted interplay and clinical implications.

Ferroptosis is a type of cell death characterized by iron-dependent phospholipid peroxidation and reactive oxygen species overproduction. Ferroptosis induces immunogenic cell death and elicits anti-tumor immune responses, playing an important role in cancer immunotherapy. Ferroptosis suppression in cancer cells impairs its immunotherapeutic efficacy. To overcome this issue, ferroptosis inducers (FINs) have been combined with other cancer therapies to create an anti-tumor immune microenvironment. However, the ferroptosis-based crosstalk between immune and tumor cells is complex because oxidative products released by ferroptotic tumor cells impair the functions of anti-tumor immune cells, resulting in immunotherapeutic resistance. In the present article, we have reviewed ferroptosis in tumor and immune cells and summarized the crosstalk between ferroptotic tumor cells and the immune microenvironment. Based on the existing literature, we have further discussed future perspectives on opportunities for combining ferroptosis-targeted therapies with cancer immunotherapies.

BMPER is a marker of adipose progenitors and adipocytes and a positive modulator of adipogenesis.

Autocrine and paracrine signaling regulating adipogenesis in white adipose tissue remains largely unclear. Here we used single-cell RNA-sequencing (RNA-seq) and single nuclei RNA-sequencing (snRNA-seq) to identify markers of adipose progenitor cells (APCs) and adipogenic modulators in visceral adipose tissue (VAT) of humans and mice. Our study confirmed the presence of major cellular clusters in humans and mice and established important sex and diet-specific dissimilarities in cell proportions. Here we show that bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) is a conserved marker for APCs and adipocytes in VAT in humans and mice. Further, BMPER is highly enriched in lineage negative stromal vascular cells and its expression is significantly higher in visceral compared to subcutaneous APCs in mice. BMPER expression and release peaked by day four post-differentiation in 3T3-L1 preadipocytes. We reveal that BMPER is required for adipogenesis both in 3T3-L1 preadipocytes and in mouse APCs. Together, this study identified BMPER as a positive modulator of adipogenesis.

Gas6/AXL pathway: immunological landscape and therapeutic potential.

Cancer is a disease with ecological and evolutionary unity, which seriously affects the survival and quality of human beings. Currently, many reports have suggested Gas6 plays an important role in cancer. Binding of gas6 to TAM receptors is associated with the carcinogenetic mechanisms of multiple malignancies, such as in breast cancer, chronic lymphocytic leukemia, non-small cell lung cancer, melanoma, prostate cancer, etc., and shortened overall survival. It is accepted that the Gas6/TAM pathway can promote the malignant transformation of various types of cancer cells. Gas6 has the highest affinity for Axl, an important member of the TAM receptor family. Knockdown of the TAM receptors Axl significantly affects cell cycle progression in tumor cells. Interestingly, Gas6 also has an essential function in the tumor microenvironment. The Gas6/AXL pathway regulates angiogenesis, immune-related molecular markers and the secretion of certain cytokines in the tumor microenvironment, and also modulates the functions of a variety of immune cells. In addition, evidence suggests that the Gas6/AXL pathway is involved in tumor therapy resistance. Recently, multiple studies have begun to explore in depth the importance of the Gas6/AXL pathway as a potential tumor therapeutic target as well as its broad promise in immunotherapy; therefore, a timely review of the characteristics of the Gas6/AXL pathway and its value in tumor treatment strategies is warranted. This comprehensive review assessed the roles of Gas6 and AXL receptors and their associated pathways in carcinogenesis and cancer progression, summarized the impact of Gas6/AXL on the tumor microenvironment, and highlighted the recent research progress on the relationship between Gas6/AXL and cancer drug resistance.

Case report: Complete pathological admission in N3 unresectable locally advanced lung adenocarcinoma with a novel INTS10-ALK and EML4-ALK fusion after neoadjuvant crizotinib.

Background: Although anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have impressive response in advanced lung adenocarcinoma with anaplastic lymphoma kinase (ALK) fusion, no guidelines point to the potential benefits of neoadjuvant ALK-TKIs for N3 unresectable locally advanced lung cancer. Current ongoing clinical trials mainly focus on the efficacy of neoadjuvant ALK-TKIs in resectable locally advanced lung cancer and ignore the role of neoadjuvant ALK-TKIs in N3 unresectable locally advanced lung cancer. Materials and methods: We report a lung cancer case with a novel INTS10-ALK and EML4-ALK rearrangement that achieved complete pathologic response to neoadjuvant crizotinib. We conducted molecular pathologic analysis by using next-generation sequencing (NGS). Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) samples and profiled using a capture-based targeted sequencing panel consisting of 56 lung cancer-related genes. Results: Our study reported a patient with stage IIIB-N3 lung adenocarcinoma with an unreported dual ALK rearrangement (INTS10-ALK and EML4-ALK) who received 5 months of crizotinib, followed by R0 right upper lobectomy, achieving complete pathological response (ypT0 ypN0). No recurrence of the tumor was found for 3 years postoperatively. Conclusion: The case supports the strategy of neoadjuvant ALK inhibitors for N3 unresectable locally advanced lung cancer, expanding the spectrum of treatment of stage IIIB-N3 lung cancer.

Correlates of chronic hepatitis B virus infection in the general adult population of China: Systematic review and meta-analysis.

Chronic infection with hepatitis B virus (HBV) is a significant public health issue in China. Understanding factors associated with chronic HBV is important to enable targeted screening and education and to improve early diagnosis and prevention of disease progression. This systematic review and meta-analysis aimed to identify and describe correlates of chronic HBV among Chinese adults. Searches were conducted in MEDLINE, EMBASE and grey literature up to 25 June 2020. Eligible papers included observational studies in adults of the general population in China that reported factors associated with chronic HBV, measured by Hepatitis B surface antigen (HBsAg). Meta-analysis was performed using fixed-effect models of HBsAg prevalence among factors, and of adjusted odds ratios (ORs) for chronic HBV associated with each factor. Overall 39 articles were included, covering 22 factors, including a range of sociodemographic, behavioural and medical factors. In meta-analysis of eligible studies, a range of factors were significantly associated with higher HBsAg prevalence, including middle age, male sex, being married, rural residence, lower education, smoking, having a HBsAg positive household contact, family history of HBV, history of surgery or blood transfusion. The adjusted ORs varied, from 1.11 (95% CI 1.05-1.18) for smoking to 5.13 (95% CI 4.99-5.26) for having a HBsAg positive household contact. In Chinese adults, a range of factors are associated with chronic HBV infection, which may help inform targeted screening in the general population.

Thunder-fire moxibustion for cervical spondylotic radiculopathy: Study protocol for a randomized controlled trial.

BACKGROUND: Thunder-fire moxibustion originated in China and contains traditional Chinese medicine. It can produce strong firepower, infrared thermal radiation, and medicinal effects when burning on the acupoints. Thunder-fire moxibustion is commonly used in patients with neck pain, but its efficacy has rarely been systematically demonstrated. We designed a randomized trial of thunder-fire moxibustion on cervical spondylotic radiculopathy (CSR) to investigate whether it is more effective than ibuprofen sustained-release capsules. METHODS: One hundred patients will be recruited and randomly divided into thunder-fire moxibustion and ibuprofen groups. The intervention consists of ten treatments and will last for 2 weeks. The Yasuhisa Tanaka 20 Score Scale is used as the primary outcome measure. It contains a combination of the self-conscious symptom in patients, objective clinical evaluation from doctors, and social evaluation (the ability to work and live). The objective and comprehensive evaluation of CSR patients before and after treatment is particularly needed. The Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2), Neck Disability Index score scale (NDI), and the Quality of Life Assessment (SF-36) are applied as secondary outcome measures. The assessment will take place at the baseline and the first and second weekends of treatment. If an adverse event (AEs) occurs, it will be reported. DISCUSSION: The aim of this trial is to determine whether thunder-fire moxibustion is more effective than ibuprofen in the treatment of patients with CSR. TRIAL REGISTRATION: Chinese Clinical Trial Registry (http://www.chictr.org.cn), ChiCTR1800018820. Registered on 11 October 2018.

Rapamycin Modulate Treg/Th17 Balance via Regulating Metabolic Pathways: A Study in Mice.

A regulatory T (Treg) cell/T helper 17 (Th17) cell imbalance is involved in many autoimmune diseases. Rapamycin (Rapa), a clinically used immunosuppressive drug, has been shown to inhibit Th17 cell differentiation but promote Treg cell generation. In this study, we aimed to study the mechanism of Rapa acting on Treg and Th17 cell differentiation. Purified mouse CD4+CD25- T cells were stimulated and polarized in vitro to generate Th17 or Treg cells in the presence or absence of Rapa. We first confirmed that Rapa inhibited the differentiation of Th17 cells and greatly promoted Treg cell generation in vitro. As metabolic pathways play a key role in T cell differentiation, we then detected the metabolic programs in Rapa-treated T cells. We found that Rapa blocked glycolysis in induced Th17 cells, evidenced by reduced glucose uptake, and inhibited expression of glucose transporter 1 and the rate-limiting enzyme HK2. In addition, the expression of c-Myc and of HIF-1α transcription factor, which regulate many genes involved in glycolysis, were inhibited by Rapa. Conversely, Rapa promoted fatty acid oxidation (FAO) metabolism in differentiated Treg cells, with the elevation of FAO product ß-hydroxybutyrate, and increased expression of ATGL and CPT1A, the key enzymes of FAO in differentiated Treg cells. The expression of phospho-AMPKα, the key signal in the regulation of FAO, was also promoted in Rapa-treated induced Treg cells. Together, these findings indicated that Rapa abrogated glycolysis in Th17 cells but facilitated FAO in induced Treg cells, which may underlie the mechanism by which Rapa regulates the Treg/Th17 balance.

HIF-1α protects against oxidative stress by directly targeting mitochondria.

The transcription factor hypoxia inducible factor-1α (HIF-1α) mediates adaptive responses to oxidative stress by nuclear translocation and regulation of gene expression. Mitochondrial changes are critical for the adaptive response to oxidative stress. However, the transcriptional and non-transcriptional mechanisms by which HIF-1α regulates mitochondria in response to oxidative stress are poorly understood. Here, we examined the subcellular localization of HIF-1α in human cells and identified a small fraction of HIF-1α that translocated to the mitochondria after exposure to hypoxia or H2O2 treatment. Moreover, the livers of mice with CCl4-induced fibrosis showed a progressive increase in HIF-1α association with the mitochondria, indicating the clinical relevance of this finding. To probe the function of this HIF-1α population, we ectopically expressed a mitochondrial-targeted form of HIF-1α (mito-HIF-1α). Expression of mito-HIF-1α was sufficient to attenuate apoptosis induced by exposure to hypoxia or H2O2-induced oxidative stress. Moreover, mito-HIF-1α expression reduced the production of reactive oxygen species, the collapse of mitochondrial membrane potential, and the expression of mitochondrial DNA-encoded mRNA in response to hypoxia or H2O2 treatment independently of nuclear pathways. These data suggested that mitochondrial HIF-1α protects against oxidative stress induced-apoptosis independently of its well-known role as a transcription factor.

Impact of obesity on the efficacy of different biologic agents in inflammatory diseases: A systematic review and meta-analysis.

OBJECTIVE: Obesity is a worldwide epidemic and a growing body of evidence suggests that it may affect the body's response to biologic agents. We investigated the influence of obesity on the efficacy of different biologic agents used to treat inflammatory diseases. METHODS: Medline, EMBASE and the Cochrane Database were searched using relevant MeSH and keyword terms for obesity and bDMARDs. Articles were selected if they reported a clinical response in obese subjects relative to other BMI categories. Response and remission outcomes were assessed using meta-analysis and all other reported outcomes were summarized. RESULTS: Among the 3850 records retrieved, 24 articles met the inclusion criteria, including 10 on rheumatoid arthritis (RA), 4 on axial spondyloarthritis (axSpA), 4 on Crohn's disease (CD), 4 on psoriasis (Ps) and 2 on psoriasic arthritis (PsA). Four biological disease-modifying anti-rheumatic drugs (bDMARDs) - anti-TNF agents, T cell co-stimulation inhibitor (abatacept), IL-6 inhibitor (tocilizumab), and B-cell depletion therapy (rituximab) - were involved. The meta-analysis showed that the odds to reach a good response or achieve remission were lower in obese (BMI>30kg/m2) than non-obese (BMI≤30kg/m2) patients who were treated with anti-TNF agents (good responder % in RA: OR 0.34, 95% CI 0.18-0.64; remission% in RA: OR 0.36, 95% CI 0.21-0.59; BASDAI50% in axSpA: OR 0.41, 95% CI 0.21-0.83), but no significant difference between obese and non-obese was found in patients treated with abatacept (good responder % in RA: OR 0.75, 95% CI 0.42-1.36; remission% in RA: OR 0.84, 95% CI 0.65-1.09) and tocilizumab (good responder % in RA: OR 1.08, 95% CI 0.44-2.63; remission% in RA: OR 0.91, 95% CI 0.50-1.66). CONCLUSION: Obesity hampered the effect of anti-TNF agents, but not those of abatacept and tocilizumab, suggesting that a personalized treatment strategy should be considered for obese patients with inflammatory diseases.

Celastrol mediates Th17 and Treg cell generation via metabolic signaling.

A T helper 17 (Th17) cell/regulatory T (Treg) cell imbalance is involved in many immune disorders and diseases. Celastrol, a Chinese herbal compound that has anti-inflammatory and immunosuppressive properties, has been indicated to suppress T cell proliferation and Th17 cell induction, while facilitating Forkhead box P3 (Foxp3) expression and Treg cell generation. In this study, we explored the impact and mechanism of celastrol on Th17 cell/induced Treg (iTreg) cell induction. CD4+CD25- T cells were purified, stimulated with anti-CD3 and anti-CD28 antibodies, and polarized in vitro to generate Th17 or iTreg cells in the presence or absence of celastrol. Initially, we determined that Interleukin (IL)-17 expression by celastrol-treated Th17 was significantly decreased compared with untreated cells; however, the frequency of Foxp3+ cells was increased in celastrol-treated cells. We verified that celastrol inhibited phospho-STAT3 expression in cultured Th17 cells and up-regulated phospho-STAT5 expression in iTreg cells. Furthermore, T cells treated with celastrol were more likely to participate in FAO metabolism instead of glycolysis. Celastrol suppressed the expression of glucose transporter, Glut1, and the rate-limiting enzyme, HK2, in addition to mTOR, HIF-1α, c-Myc and Akt expression in Th17 cells. Conversely, celastrol promoted FAO of lipids by up-regulating CPT1A and AMPKα expression in iTreg cells. Our results suggest that celastrol suppresses Th17 cell induction, while promoting the generation of iTreg cells. We found that celastrol inhibits glycolysis in Th17 cells and promotes FAO by iTreg cells, suggesting that celastrol could mediate the metabolism of Th17 and iTreg cells.