ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages.

BACKGROUND: Understanding the mechanisms that mediate the interaction between tumor and immune cells may provide therapeutic benefit to patients with cancer. The N6-methyladenosine (m6A) demethylase, ALKBH5 (alkB homolog 5), is overexpressed in non-small cell lung cancer. However, its role in the tumor microenvironment is unknown. METHODS: Datasets and tissue samples were used to determine the relationship between ALKBH5 expression and immunotherapy efficacy. Bioinformatic analysis, colorimetric assay to determine m6A RNA methylation, dual luciferase reporter assay, RNA/m6A-modified RNA immunoprecipitation, RNA stability assay, and RNA sequencing were used to investigate the regulatory mechanism of ALKBH5 in non-small cell lung cancer. In vitro and in vivo assays were performed to determine the contribution of ALKBH5 to the development of non-small cell lung cancer. RESULTS: ALKBH5 was upregulated in primary non-small cell lung cancer tissues. ALKBH5 was positively correlated with programmed death-ligand 1 expression and macrophage infiltration and was associated with immunotherapy response. JAK2 was identified as a target of ALKBH5-mediated m6A modification, which activates the JAK2/p-STAT3 pathway to promote non-small cell lung cancer progression. ALKBH5 was found to recruit programmed death-ligand 1-positive tumor-associated macrophages and promote M2 macrophage polarization by inducing the secretion of CCL2 and CXCL10. ALKBH5 and tumor-associated macrophage-secreted IL-6 showed a synergistic effect to activate the JAK2/p-STAT3 pathway in cancer cells. CONCLUSIONS: ALKBH5 promotes non-small cell lung cancer progression by regulating cancer and tumor-associated macrophage behavior through the JAK2/p-STAT3 pathway and the expression of CCL2 and CXCL10, respectively. These findings suggest that targeting ALKBH5 is a promising strategy of enhancing the anti-tumor immune response in patients with NSCLC and that identifying ALKBH5 status could facilitate prediction of clinical response to anti-PD-L1 immunotherapy.

STING mediates LPS-induced acute lung injury by regulating ferroptosis.

The pathogenesis of acute lung injury is not fully understood. Stimulator of interferon genes (STING) and ferroptosis have been implicated in various pathological and physiological processes, including acute lung injury (ALI). However, the relationship between STING and ferroptosis in lipopolysaccharide (LPS)-induced ALI is unclear. We found that LPS stimulation activated STING and ferroptosis. Furthermore, STING knockout and ferroptosis inhibitor alleviated lung inflammation and epithelial cell damage. Also, STING knockout reduced inflammation injury and ferroptosis. Notably, the ferroptosis inducer reversed the alleviation of inflammation caused by STING knockout. These results show that STING participates in the inflammation injury of ALI by regulating ferroptosis. Results also showed that p-STAT3 levels increased after STING knockout, suggesting that STING negatively regulates STAT3 activation. Besides, STAT3 inhibitor aggravated ferroptosis after STING knockout, indicating that STING regulates ferroptosis through STAT3 signaling. In conclusion, STING mediates LPS-induced ALI by regulating ferroptosis, indicating that STING and ferroptosis may be new targets for ALI treatment.

Efficacy and safety of first-line PD-1/PD-L1 inhibitor combinations for extensive-stage small-cell lung cancer: a Bayesian network meta-analysis.

Objectives: Several randomized controlled trials (RCTs) indicated that first-line programmed cell death protein-1/death-ligand 1 inhibitors plus chemotherapy (PD-1/PD-L1 + chemo) led to survival benefits in extensive-stage small-cell lung cancer (ES-SCLC) compared with platinum-based chemotherapy. This study aims to identify the optimal PD-1/PD-L1 + chemo combination strategy. Methods: We included RCTs comparing PD-1/ PD-L1 + chemo versus chemo alone in ES-SCLC. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade ⩾3 treatment-related adverse events were considered. Odds ratios (ORs), hazard ratios (HRs), and their 95% confidence intervals (CIs) were extracted. Results: Six RCTs with 2600 patients were analyzed in this Bayesian network meta-analysis. Results showed that adding PD-1/PD-L1 inhibitors to chemotherapy led to significant benefits in OS (HR = 0.72, 95% CI: 0.66-0.79), PFS (HR = 0.69, 95% CI: 0.63-0.75), and ORR (OR = 1.32, 95% CI: 1.12-1.56), and no differences in toxicity were found (OR = 1.09, 95% CI: 0.92-1.30). Serplulimab plus chemotherapy was found to provide the best OS (HR = 0.63, 95% CI: 0.49-0.82), the best PFS (HR = 0.47, 95% CI: 0.38-0.59), and the best ORR (OR = 1.7, 95% CI: 1.15-2.53). Moreover, although there were no difference between PD-L1 + chemo and PD-1 + chemo regarding OS (HR = 0.99, 95% CI: 0.91-1.08) and ORR (OR = 1.27, 95% CI: 0.91-1.78), PD-1 + chemo showed a significant benefit in PFS (HR = 0.82, 95% CI: 0.68-0.98) compared with PD-L1 + chemo. Conclusions: Serplulimab plus chemotherapy seems to be superior first-line immunotherapy combination for patients with ES-SCLC. PD-1 + chemo seems to outperform PD-L1 + chemo in PFS.

Neoadjuvant alectinib in locally advanced lung adenocarcinoma with anaplastic lymphoma kinase rearrangement: case series and literature review.

In view of the success of targeted therapy in the field of advanced lung cancer, it is gradually pushed further to neoadjuvant therapy. Alectinib has been recommended for advanced anaplastic lymphoma kinase (ALK) + non-small cell lung cancer (NSCLC) in first-line therapy. Here, we report two cases of neoadjuvant alectinib in locally advanced lung adenocarcinoma with ALK rearrangement. Case 1 was a 64-year-old man with no history of smoking who was diagnosed with the clinical stage as IIIB, with ALK fusion-positive. Chest-enhanced computed tomography (CT) revealed marked regression and achieved partial response (PR) incorporated with grade 3 interstitial pneumonia after 44 days of alectinib neoadjuvant therapy. Interstitial pneumonia improved after methylprednisolone therapy, then thoracoscopic lobe resection with lymph node dissection was performed with blood loss. The pathological assessment was a pathologic complete response(pCR). Case 2 was a 66-year-old man who had a routine physical examination and then diagnosed with a clinical-stage IIIB by CT-guided percutaneous cutting needle biopsy (PCNB). Chemotherapy with 1 cycle of pemetrexed combined with nedaplatin was performed in the interval waiting for next-generation sequencing (NGS) results. NGS testing revealed an EML4-ALK fusion mutation. After 109 days of alectinib treatment, radiographic evaluation was classified as PR and then he underwent thoracoscopic upper lobectomy smoothly with pathological assessment as a major pathological response (MPR). To date, neoadjuvant alectinib has only been reported in a few cases in locally advanced lung adenocarcinoma with ALK-rearranged. Neoadjuvant alectinib may be feasible in locally advanced disease for complete resection. The duration and safety of neoadjuvant therapy with alectinib still need further study.

Comparison between immunotherapy efficacy in early non-small cell lung cancer and advanced non-small cell lung cancer: a systematic review.

BACKGROUND: Currently, immunotherapy is widely used in the treatment of various stages of non-small cell lung cancer. According to clinical experience and results of previous studies, immunotherapy as neoadjuvant therapy seems to exhibit better efficacy against early resectable non-small cell lung cancer as compared to advanced lung cancer, which is often defined as unresectable non-small cell lung cancer. However, this observation has not been established in clinical studies. This systematic review aimed to evaluate the efficacy of immunotherapy in early and late lung cancer, wherein objective response rate (ORR) and disease control rate (DCR) were used as evaluation indexes. The present study also evaluated the safety of immunotherapy in early and late lung cancer, wherein the rate of treatment-related adverse reactions (TRAEs) was used as an indicator. METHODS: Electronica databases, including PubMed, Cochrane Library, Embase, and other databases, were searched to identify relevant studies. Besides this, all the available reviews, abstracts, and meeting reports from the main international lung cancer meetings were searched manually. ORR, DCR, and TRAEs were extracted as the primary outcomes. RESULTS: A total of 52 randomized controlled trials involving 13,660 patients were shortlisted. It was observed that immunotherapy alone significantly improved DCR in early lung cancer in comparison to advanced lung cancer. Importantly, the improvement in ORR was not to the same extent as reported in the case of advanced lung cancer. The combination of immunotherapy with other therapies, especially immunochemotherapy, significantly improved ORR and DCR in early lung cancer. In terms of safety, immunotherapy either alone or in combination with other therapies exhibited a better safety profile in early lung cancer than in advanced lung cancer. CONCLUSIONS: Altogether, the benefits of immunotherapy in early lung cancer appeared to be better than those observed in advanced lung cancer, especially with the regard to the regimen of immunotherapy in combination with chemotherapy. In terms of safety, both immunotherapy alone and its combination with chemotherapy were found to be safer in early lung cancer as compared to advanced lung cancer.

Analysis of M6A associated lncRNAs in prognosis and immune response of NSCLC patients.

Distinguishing between N6-methyladenosine (m6A)-associated long noncoding RNAs (lncRNAs) is crucial in non-small-cell lung cancer (NSCLC) patients. In this research, the prognosis and immunotherapeutic response of lncRNAs and m6A in NSCLC were examined. lncRNAs related to m6A were identified using co-expression analyses, and their prognostic impact on patients with NSCLC was assessed using univariate Cox regression analysis. Sixty-three m6A-associated lncRNAs were determined as prognostic lncRNAs, and on this basis, 25 m6A-associated lncRNAs were screened by least absolute shrinkage and selection operator (lasso) Cox regression. Multivariable Cox analysis obtained 14 m6A-associated lncRNAs for the construction of risk model. The NSCLC patients were grouped into different risk subgroups in accordance with the median of the risk fraction in each data, and we evaluated the differences of potential immunotherapeutic characteristics and drug sensitivity prediction between the two subgroups. By using this model to recombine patients, they can be effectively distinguished in terms of the immunotherapy response. Furthermore, candidate compounds for the differentiation of NSCLC subtypes were identified. The model based on 14 m6A-associated lncRNAs is a promising prognostic biomarker, which may help to predict the efficacy of immunotherapy in NSCLC patients and provide a theoretical basis for improving the outcome of patients.

A Multicenter Retrospective Study on the Prognosis of Stage III Unresectable Mutant Non-Small Cell Lung Cancer With Tyrosine Kinase Inhibitors Therapy.

BACKGROUND: For unresectable stage III non-small cell lung cancer (NSCLC), concurrent chemoradiotherapy is nowadays the standard treatment. Patients with advanced NSCLC harboring driver-gene mutations benefit from Tyrosine Kinase Inhibitors (TKIs) Therapy. In a real-world setting, there is room for exploring the benefit of TKIs in stage III unresectable NSCLC patients with mutation. METHODS: A total of 81 patients from the Jinling Hospital and the Jiangsu Cancer Hospital with stage III unresectable mutant NSCLC applied targeted therapy were enrolled in this retrospective study. Patients with first-line application of TKIs were followed up to gain the situation of surgery qualifications, progression-free survival and overall survival, so as to evaluate the survival prognosis, then whether patients benefit and what kind of patients benefit most from TKI monotherapy treatment or its combination are explored. RESULTS: The median progression-free survival of involved 81 patients was 13.87 months (95% confidence interval (CI): 11.66-16.08), and the median survival was 41.47 months (95%CI: 20.11-62.83). The 5-year survival rates were 91.0, 80.3, 56.1, 45.5, and 32.5%, respectively. After first-line TKI therapy, seven patients (8.6%) were reevaluated as eligible for surgery and proceeded to surgery. Although no characteristics were found to be statistical prognostic, younger female non-smokers still tended to have a better prognosis with longer progression free survival and overall survival. CONCLUSIONS: TKIs are a viable option for mutant stage III unresectable NSCLC patients who have achieved good clinical benefit from TKI. Patients who cannot tolerate chemoradiotherapy, especially those with driver gene mutations, can choose targeted therapy for first-line treatment.

A narrative review of advances in treatment and survival prognosis of HER2-positive malignant lung cancers.

Human epidermal growth factor receptor 2 (HER2), as a receptor tyrosine kinase of EGF receptor family, whose mutation is often associated with even if less frequency but poor prognosis and shorter survival in pulmonary malignant tumor. HER2 status include mutation, overexpression, amplification and also some rare genotypes, detected by next generation sequencing (NGS), immunohistochemistry (IHC), and also fluorescence in situ hybridization (FISH). Different genotypes represent different therapeutic targets and indicate different clinical prognosis concluded by previous studies. Unfortunately, no standard guidelines for first-line treatment are widely recognized, and current therapeutic schedules include chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Especially for patients with advanced metastasis, chemotherapy is based as a systemic therapy using studies of breast cancer or EGFR-positive lung adenocarcinoma as a template. Studies already explored treatment including EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and afatinib, and also trastuzumab and its conjugation like HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) and conjugate trastuzumab deruxtecan (T-DXd). Also, he researches explored combination therapy with chemotherapy and TKIs or monoclonal antibodies. This review describes commonly used therapies for HER2-positive/HER2-overexpression patients and general relationship between genotypes of HER2, drug selection and final prognosis in order to provide suggestions for future diagnosis and treatment.

Metastasis-associated fibroblasts: an emerging target for metastatic cancer.

Metastasis suggests a poor prognosis for cancer patients, and treatment strategies for metastatic cancer are still very limited. Numerous studies have shown that cancer-associated fibroblasts (CAFs), a large component of the tumor microenvironment, contribute to tumor metastasis. Stromal fibroblasts at metastatic sites are different from CAFs within primary tumors and can be termed metastasis-associated fibroblasts (MAFs), and they also make great contributions to the establishment of metastatic lesions and the therapeutic resistance of metastatic tumors. MAFs are capable of remodeling the extracellular matrix of metastatic tumors, modulating immune cells in the tumor microenvironment, promoting angiogenesis and enhancing malignant tumor phenotypes. Thus, MAFs can help establish premetastatic niches and mediate resistance to therapeutic strategies, including immunotherapy and antiangiogenic therapy. The results of preclinical studies suggest that targeting MAFs can alleviate the progression of metastatic cancer and mitigate therapeutic resistance, indicating that MAFs are a promising target for metastatic cancer. Here, we comprehensively summarize the existing evidence on MAFs and discuss their origins, generation, functions and related therapeutic strategies in an effort to provide a better understanding of MAFs and offer treatment perspectives for metastatic cancer.

A narrative review of progress in diagnosis and treatment of small cell lung cancer patients with hyponatremia.

Small cell lung cancer (SCLC) is one of the malignant cancers of lung tumors, and hyponatremia, defined as serum sodium concentration (Na+) lower than 135 mmol/L, is the most common complication of solid tumors, with an incidence of up to 18.9% and a negative impact on quality of life in SCLC. As a prognostic index of SCLC, timely monitoring and correcting of hyponatremia is of great clinical significance for prolonging the survival period of patients. In the explore of new drugs for small cell lung cancer, it is necessary to include hyponatremia as an evaluation index in clinical studies. As the occurrence of hyponatremia is sometimes unavoidable owing to SCLC specific neurological characteristics, early monitoring to detect the presence of hyponatremia and timely correction are helpful to improve the prognosis of patients. There are many predisposing factors for hyponatremia, including heterotopia of antidiuretic hormone (ADH), use of platinum-based chemotherapy drugs, and intracranial metastasis, among others. Patients with small cell lung cancer are usually asymptomatic in the early stage, while it is of great significance to find a suitable clinical index to judge whether it is a malignant inducement or not. In the clinical setting, due to different electrolyte levels and therapeutic scheduling for the primary disease, an individualized plan is often made, mainly comprising water restriction, infusion, and medications. This review includes related clinical studies and describes the common symptoms and predisposing factors of hyponatremia in patients with SCLC, and their impact on quality of life and prognosis.