CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear. PATIENTS AND METHODS: In this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC. RESULTS: The proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders' peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis. CONCLUSION: CD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression.

CD57-positive CD8 + T cells define the response to anti-programmed cell death protein-1 immunotherapy in patients with advanced non-small cell lung cancer.

Immune checkpoint inhibitors have transformed the treatment landscape of non-small cell lung cancer (NSCLC). However, accurately identifying patients who will benefit from immunotherapy remains a challenge. This study aimed to discover potential biomarkers for predicting immunotherapy response in NSCLC patients. Single-cell mass cytometry (CyTOF) was utilized to analyze immune cell subsets in peripheral blood mononuclear cells (PBMCs) obtained from NSCLC patients before and 12 weeks after single-agent immunotherapy. The CyTOF findings were subsequently validated using flow cytometry and multiplex immunohistochemistry/immunofluorescence in PBMCs and tumor tissues, respectively. RNA sequencing (RNA-seq) was performed to elucidate the underlying mechanisms. In the CyTOF cohort (n = 20), a high frequency of CD57+CD8+ T cells in PBMCs was associated with durable clinical benefit from immunotherapy in NSCLC patients (p = 0.034). This association was further confirmed in an independent cohort using flow cytometry (n = 27; p < 0.001), with a determined cutoff value of 12.85%. The cutoff value was subsequently validated in another independent cohort (AUC = 0.733). We also confirmed the CyTOF findings in pre-treatment formalin-fixed and paraffin-embedded tissues (n = 90; p < 0.001). RNA-seq analysis revealed 475 differentially expressed genes (DEGs) between CD57+CD8+ T cells and CD57-CD8+ T cells, with functional analysis identifying DEGs significantly enriched in immune-related signaling pathways. This study highlights CD57+CD8+ T cells as a promising biomarker for predicting immunotherapy success in NSCLC patients.

Blood tumor mutation burden can predict the clinical response to immune checkpoint inhibitors in advanced non-small cell lung cancer patients.

BACKGROUND: Tissue tumor mutation burden (tTMB) assessed by whole-exome sequencing (WES), which has been regarded as the gold standard method of tTMB measurement, can predict the clinical benefits of immune checkpoint inhibitors (ICIs). Multiple studies have investigated the feasibility of utilizing large panels to evaluate TMB but have obtained conflicting results. Furthermore, whether blood TMB (bTMB) can also be a predictive biomarker in NSCLC has not been determined. METHODS: Fifty-six advanced NSCLC patients treated with ICIs were enrolled, including an exploratory cohort (n = 42) and a small independent validation cohort (n = 14). Next-generation sequencing was performed on tumor and plasma samples collected prior to ICI treatment using a panel consisting of 520 cancer-related genes (OncoScreen) to evaluate tTMB/bTMB. WES was also performed on tumor samples to serve as references. RESULTS: A positive correlation between tTMB derived from WES and OncoScreen was observed. OncoScreen-derived tTMB showed a positive correlation with OncoScreen-derived bTMB. Patients with OncoScreen-derived tTMB [Formula: see text] 7 mutations/Mb (p = 0.003) or bTMB [Formula: see text] 11 mutations/Mb (p = 0.0029) had superior progression-free survival (PFS). In the small validation cohort, patients with OncoScreen-derived bTMB [Formula: see text] 11 mutations/Mb exhibited longer PFS (p = 0.192) with a nonsignificant difference. In all 42 patients who had available bTMB and PFS, patients with bTMB [Formula: see text] 11 mutations/Mb had significantly longer PFS (p = 0.011) than those with bTMB [Formula: see text] 11 mutations/Mb. CONCLUSION: Our study confirmed the feasibility of using large panels to estimate TMB. We also demonstrated that bTMB can serve as a potential biomarker for predicting the efficacy of ICIs in NSCLC.

Dioscin elicits anti-tumour immunity by inhibiting macrophage M2 polarization via JNK and STAT3 pathways in lung cancer.

Tumour-associated macrophage (TAM) is an important component in tumour microenvironment. Generally, TAM exhibits the function of M2-like macrophage, which was closely related to angiogenesis and tumour progression. Dioscin, a natural steroidal saponin, has shown its powerful anti-tumour activity recently. However, the mechanism of dioscin involved in immune regulation is still obscure. Here, we observed dioscin induced macrophage M2-to-M1 phenotype transition in vitro and inhibited IL-10 secretion. Meanwhile, the phagocytosis of macrophages was enhanced. In subcutaneous lung tumour models, dioscin inhibited the augmentation of M2 macrophage populations. Furthermore, dioscin down-regulated STAT3 and JNK signalling pathways in macrophages in vitro. In BMDMs, activating JNK and inhibiting STAT3 induce macrophages to M1 polarization while inhibiting JNK and activating STAT3 to M2 polarization. Additionally, condition mediums from dioscin-pre-treated macrophages inhibited the migration of 3LL cells and the tube-formation capacity of HUVECs. What's more, dioscin-mediated macrophage polarization inhibited the in vivo metastasis of 3LL cells. In conclusion, dioscin may act as a new anti-tumour agent by inhibiting TAMs via JNK and STAT3 pathways in lung cancer.

Recurrent eosinophilic pleuritis caused by sparganum infection: A case report and review of the literature.

RATIONALE: Sparganosis is an infectious disease caused by a larval tapeworm of the genus Spirometra, which commonly invades subcutaneous tissues. Pulmonary and pleural involvement due to sparganum has been rarely reported previously. PATIENT CONCERNS: We herein described a case of recurrent eosinophilic pleuritis in a 24-year-old woman. She was admitted with persistent cough and shortness of breath for more than 1 month. Initial chest computed tomography scan suggested right pleural effusion and diffuse pleural thickening. Slightly elevated eosinophil counts were found in both the peripheral blood and pleural fluid. She underwent right pleurectomy but histological examination failed to obtain an etiological diagnosis. Moreover, eosinophilic pleural effusion re-appeared in the contralateral thoracic cavity one month later. After re-admission, we reviewed her medical history meticulously and found she had a history of ingesting raw snake gallbladders before hospitalization. The final diagnosis was confirmed by the markedly positive reaction against sparganum antigen in both serum and pleural fluid sample. DIAGNOSIS: Eosinophilic pleuritis caused by sparganum infection. INTERVENTIONS: After the diagnosis, the patient was treated with praziquantel at 75 mg/kg/d for 3 days. OUTCOMES: Pleural effusion absorbed completely and eosinophil count in peripheral blood returned to normal range. No evidence of recurrent pleural effusion had been observed in over one year of follow-up. LESSONS: Clinicians need to be aware the possibility of sparganum infection in cases of eosinophilic pleuritis. The specific enzyme-linked immunosorbent assay remains a useful method in acquiring a rapid diagnosis, especially when histological examination is unable to detect the larvae in the thoracic cavity.

Extrapontine myelinolysis caused by rapid correction of pituitrin-induced severe hyponatremia: A case report.

BACKGROUND: Severe hyponatremia is considered a rare complication of pituitrin, which is widely used for the treatment of pulmonary hemorrhage. However, the management of pituitrin-associated hyponatremia can be challenging because a rapid correction of hyponatremia may cause the development of osmotic demyelination syndrome, resulting in life-threatening neurological injuries. CASE SUMMARY: A 20-year-old Chinese man with massive hemoptysis developed symptomatic hyponatremia (116 mmol/L) after therapy by a continuous intravenous drip of pituitrin. To normalize his serum sodium, a hypertonic saline infusion was applied for 3 d, and the pituitrin administration was stopped concurrently. Then, an overly rapid increase in serum sodium level (18 mmol/L in 24 h) was detected after treatment. One day later, the patient experienced a sudden onset of generalized tonic-clonic seizures, as well as subsequent dysarthria and dystonia. Magnetic resonance imaging revealed increased signal intensity in the bilateral symmetric basal ganglia on the T2-weighted images, compatible with a diagnosis of extrapontine myelinolysis. The patient received an intravenous administration of high-dose corticosteroids, rehabilitation, and neurotrophic therapy. Finally, his clinical abnormalities were vastly improved, and he was discharged with few residual symptoms. CONCLUSION: Physicians should be fully aware that pituitrin can cause profound hyponatremia and its correction must be performed at a controlled rate to prevent the development of osmotic demyelination syndrome.

Clinical Characteristics and Outcomes of Acute Lung Injury Caused by Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Retrospective Cohort Study from a Single Institution in China.

BACKGROUND: Acute lung injury (ALI) is a rare but life-threatening pulmonary complication of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The aim of this study was to characterize the common risk factors, clinical features, imaging findings, treatments, and outcomes of acute lung injury caused by TACE. METHODS: A retrospective study was performed on all TACE-associated ALI cases that were diagnosed at authors' hospital from January 2015 to June 2018. RESULTS: The study included 14 ALI cases where the mean age of patients was 60.9 ± 11.7 years (range 41-82 years), with a mean onset time of 2.4 ± 1.6 d after TACE. Of the 14 patients, 8 patients (57.1%) developed acute respiratory distress syndrome (ARDS). 7 patients (50%) had underlying chronic respiratory disease and hepatic arteriovenous fistula was detected in 6 patients (42.6%), both of which were significantly higher than control group (P < 0.05). Dyspnea (92.9%) was the most common symptoms. Pleural effusion (64.3%), diffuse pulmonary infiltration (42.9%), and accumulation of Lipiodol in lung field (42.9%) were frequent radiologic abnormalities. 11 patients (78.6%) achieved remission after treatment, and the 30-day mortality rate was approximately 21.4%. Patient's median survival time after the development of ALI was merely 4.3 months, which was obviously worse than control group (4.3 months vs. 13.5 months, P < 0.05). CONCLUSION: This study illustrates that TACE-associated ALI is a rare pulmonary complication with a high mortality rate. We infer that pulmonary Lipiodol embolization might be one of the main causes of TACE-associated ALI. Thus, HCC patients who are at high risk should be closely evaluated and monitored during TACE to avoid such potentially fatal complication.

Honokiol induces apoptosis of lung squamous cell carcinoma by targeting FGF2-FGFR1 autocrine loop.

Lung squamous cell carcinoma (SCC) accounts for a considerable proportion of lung cancer cases, but there is still a lack of effective therapies. FGFR1 amplification is generally considered a promising therapeutic target. Honokiol is a chemical compound that has been proven to be effective against various malignancies and whose analog has been reported to target the mitogen-activated protein kinase family, members of a downstream signaling pathway of FGFR1. This was an explorative study to determine the mechanism of honokiol in lung SCC. We found that honokiol induced apoptosis and cell cycle arrest in lung SCC cell lines in a time- and dose-dependent manner. Honokiol also restricted cell migration in lung SCC cell lines. Moreover, the expression of FGF2 and the activation of FGFR1 were both downregulated by honokiol. Pharmacological inhibition and siRNA knockdown of FGFR1 induced apoptosis in lung SCC cells. Our in vivo study indicated that honokiol could suppress the growth of xenograft tumors, and this effect was associated with the inhibition of the FGF2-FGFR1 signaling pathway. In conclusion, honokiol induced cell apoptosis in lung SCC by targeting the FGF2-FGFR1 autocrine loop.

Expression level of long noncoding RNA H19 in plasma of patients with nonsmall cell lung cancer and its clinical significance.

OBJECTIVE: This study was aimed to explore the expression level of long noncoding RNA H19 in the plasma of patients with nonsmall cell lung cancer (NSCLC) and its clinical significance. METHODS: A total of 66 NSCLC patients (case group) and 31 patients with benign lung disease (control group) admitted from February 2015 to February 2017 were included in this study. Real-time polymerase chain reaction assay was applied to examine the relative expression level of long noncoding RNA H19 in the plasma of the two groups. The relationship between H19 expression and clinical, pathological features was explored. Receiver-operating characteristic (ROC) curve was applied to evaluate the clinical value of plasma H19 as a tumor marker in the auxiliary diagnosis of NSCLC. RESULTS: The relative expression levels of plasma H19 inpatients from NSCLC group and benign lung disease group were 5.62 ± 2.02 (ΔCt) and 7.74 ± 2.75 (ΔCt), respectively. The NSCLC group presented with significantly higher levels than that of the benign disease group (P < 0.05). According to the median of relative expression level of 5.54, the plasma H19 of NSCLC patients was classified into low expression group ≥5.54 (n = 34) and high expression group <5.52 (n = 32). The relationship between the patients' clinical, pathological features, and the expression level of H19 was analyzed. The expression of H19 was not significantly correlated with the gender, age, clinical staging, tumor diameter, and pathological type of the patients (Pall > 0.05). With the serum H19 as a diagnosis reference, the diagnostic sensitivity of NSCLC was 67.74%, and the specificity was 63.08%. The area under the ROC curve was 0.73, and the diagnostic cutoff value was 6.62. CONCLUSION: Plasma level of H19 in NSCLC patients was significantly increased, which could be applied as a serological marker for the auxiliary diagnosis of NSCLC.

Sesquiterpene lactone parthenolide markedly enhances sensitivity of human A549 cells to low-dose oxaliplatin via inhibition of NF-kappaB activation and induction of apoptosis.

Aberrant activation of NF-kappaB has been proposed as the major cause of chemoresistance in lung cancer. Low-dose chemotherapeutic agents with limited toxicity and achieving profoundly enhanced efficacy by blocking NF-kappaB activation may be a useful strategy in cancer therapy. Thus, this study was performed to explore the effect of parthenolide, a natural NF-kappaB inhibitor, on human lung cancer A549 cells treated with low-dose oxaliplatin, as well as to determine the potential mechanisms involved. We incubated A549 cells with different concentrations of parthenolide in the absence or presence of a low-dose of oxaliplatin for 48 h. Then, cell proliferation was determined by MTT assay, and flow cytometry was used to study apoptosis. PGE(2) production in culture supernatants was detected by competitive ELISA, while expression of NF-kappaB/p65, COX-2, caspase-3 and caspase-9 proteins were analyzed by Western blot. Finally, compared to parthenolide or oxaliplatin alone, significant improvements in cell apoptosis and growth inhibition indexes were observed in the combined treatment. NF-kappaB/p65, COX-2, and PGE(2) expression were suppressed by the co-application; meanwhile, caspase-3 and caspase-9 proteins were obviously activated. These findings indicate that parthenolide could markedly enhance sensitivity of A549 cells to low-dose oxaliplatin by inhibiting NF-kappaB activation and inducing apoptosis. Parthenolide in combination with a low dose of oxaliplatin may be a beneficial chemotherapeutic strategy for patients who cannot tolerate the severe side effects of the drug at therapeutic concentrations.