Translational lung cancer research最新文献

Background: Therapeutic strategies to engage anti-tumor innate immunity are still underdeveloped. Imprime PGG (imprime), a pathogen-associated molecular pattern (PAMP), through pattern recognition receptors, successfully illicit a broad-based innate immune response in preclinical models against various cancers. We aimed to study safety and efficacy of imprime in combination with pembrolizumab in advanced stage non-small cell lung cancer (NSCLC).

Methods: We conducted an investigator-initiated, multi-institutional, single-arm, phase Ib/II trial in previously treated, advanced stage NSCLC patients. Primary endpoints were maximum-tolerated dose (MTD) of imprime for the phase Ib, and progression-free survival (PFS) for the phase II study (NCT03003468).

Results: All 33 eligible patients were included in the safety analysis. No dose-limiting toxicity was observed and the imprime dose of 4 mg/kg was determined as the MTD. Thirty patients treated at the MTD (phase Ib, 6; phase II, 24) were included in the efficacy analysis. Median length of follow-up was 10.8 months. Confirmed objective response rate was 10% [95% confidence interval (CI): 2-27%], with one complete and two partial responses. Median PFS was 2.6 months (95% CI: 1.4-7.0), and 6- and 12-month PFS rates were 37% and 17%, respectively. Median overall survival (OS) was 11.1 months, and 6- and 12-month OS rates were 75% and 46%. Univariate analysis was performed to assess the impact of age, sex, race, disease-stage, programmed death-ligand 1 (PD-L1) expression levels, and prior immunotherapy on PFS and OS. Of these, prior immunotherapy negatively influenced OS [hazard ratio (HR): 2.95, 95% CI: 1.21-7.24]. Overall, the combination was safe and tolerable.

Conclusions: The combination of imprime and pembrolizumab is tolerable but did not improve the outcome of advanced stage NSCLC patients who previously progressed on anti-programmed death 1 (PD-1)/PD-L1 immunotherapies. Further investigation is needed to understand the effects of therapeutic PAMPs to mount a strong innate immune response against cancer.

Background: Identifying biomarkers to predict responses for neoadjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC) is under intensive study. Considering the interplay between cancer, inflammation, and immunosuppression, we hypothesized that circulating and imaging inflammatory markers could serve as indicators of anti-tumor immune responses, and thus conducting an exploratory study to reveal the predictive value of combining longitudinal systemic inflammatory markers in stratifying pathologic response to neoadjuvant sintilimab.

Methods: We retrospectively reviewed 36 patients (29 male and seven female) with NSCLC (stage IA-IIIB) who underwent pre- and post-treatment peripheral blood tests and ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) scans before and after two cycles of neoadjuvant sintilimab (registration number: ChiCTR-OIC-17013726). The neutrophil-to-lymphocyte ratio (NLR), immune-related adverse events (irAEs) on imaging, and lymphoid organ metabolism [spleen-to-liver ratio (SLR) and bone marrow-to-liver ratio (BLR)] were evaluated to examine their predictive value for the major pathologic response (MPR). Significant variables were used to classify patients into low, intermediate, and high inflammatory burden groups for stratifying pathologic regression and tumor-infiltrating immune cells abundance in the tumor microenvironment. Spearman's correlation analysis was performed to explore the correlation between systemic inflammatory markers, primary tumor metabolism, and tumor-infiltrating immune cells abundance at various time points.

Results: Of the 36 enrolled patients, 13 (36.1%) exhibited MPR. ΔNLR% was a significant negative predictor of MPR (P=0.047) and negatively correlated with pathologic regression (r=-0.34, P=0.045). Pre- and post-treatment SLRs were potential negative predictors of MPR (P=0.06; P=0.055) and negatively correlated with pathologic regression (r=-0.30, P=0.07; r=-0.31, P=0.06). The high inflammatory burden group (pre-treatment SLR >0.83 and ΔNLR% >-17%) had the lowest pathologic regression (P=0.01) and the highest infiltration abundance of pre-treatment CD68⁺ macrophage (P=0.01-0.04). irAEs on imaging did not have significant effects on MPR and pathologic regression in overall and per-organ analyses.

Conclusions: The combination of pre-treatment SLR and ΔNLR% demonstrates predictive value in stratifying pathologic response to neoadjuvant immunotherapy in resectable NSCLC. The high inflammatory burden group had the lowest pathologic regression and the pre-treatment immunosuppressive microenvironment with macrophage enrichment.

Background: Epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) gene mutations are well established in the pathogenesis of non-small cell lung cancer (NSCLC). However, there is limited understanding about the impact of rare variants, such as EGFR exon 20 insertion mutation (EGFRex20ins) and MET exon 14 skipping mutation (METex14) in the Chinese population even though targeted therapies have been approved in China. We conducted a scoping review to assess the current available evidence of these two mutations in NSCLC in the Chinese population.

Methods: Electronic searches were performed before November 2023. Two investigators independently collected data. Any discrepancies were resolved through discussion with a senior investigator.

Results: We identified 111 studies, involving a total of 159,993 NSCLC Chinese patients. Of the 111 studies, 76 studies reported on EGFRex20ins and 45 reported on METex14. When we evaluated the frequency from studies with at least 1,000 patients, the frequency of EGFRex20ins ranged from 0.02-2.85% of all NSCLC patients and 0.56-6.90% of all EGFR mutations. The frequency of METex14 ranged from 0.08-1.38% of all NSCLC patients and 8.33-56.60% of all MET mutations. The treatments for NSCLC with EGFRex20ins varied depending on the study, and all available treatments have limited therapeutic efficacy and a relatively poor prognosis, and fewer studies have examined the efficacy and effectiveness of treatments for NSCLC with METex14 mutation in the Chinese population.

Conclusions: Despite the recent approval of three targeted therapies in China, there is still insufficient evidence regarding their optimal treatment and therapeutic efficacy for Chinese patients. Further large-scale studies are needed to establish links between these mutations and clinical features at baseline and following treatment. Furthermore, moving forward, the development of novel drugs will be essential to fulfill the clinical unmet needs.

Background: Circulating tumor cells (CTCs) provide a unique resource to decipher cell molecular properties of lung cancer. However, the clinicopathologic and radiological features associated with CTCs in different lung cancer subtypes remain poorly characterized. The aim of this study was to explore the clinicopathological and radiological features of CTCs in different lung cancer subtypes.

Methods: The CTC data were obtained using the CellSearch Circulating Tumor Cell Kit. CTCs were detected in 5,128 surgical patients with lung adenocarcinoma (LUAD), 2,226 with lung squamous cell carcinoma (LUSC), 248 with small cell lung cancer (SCLC), 99 with large cell carcinoma, and 70 with metastatic carcinomas. A Pearson correlation analysis was conducted to analyze the patients' clinical information, radiological features, and molecular characteristics, and logistic regression was used to examine the correlations between these factors and CTCs.

Results: For LUAD, the presence of tumor lobation, air bronchogram, and the epidermal growth factor receptor (EGFR) mutation were significantly associated with CTC levels. While the multivariable logistic regression analysis indicated that CD68 and P40 expression were independent factors associated with CTCs. For LUSC, tumor size, tumor spiculation, pleural indentation, air bronchogram, the expression levels of CK8/18, GPA33, and leucocyte common antigen (LCA) were significantly associated with CTC levels. The multivariable logistic regression analysis indicated that tumor size, pleural indentation, and air bronchogram were independent factors affecting CTCs. For SCLC, no factors were found to be significantly associated with CTC levels. For large cell carcinoma, tumor lobation and spiculation were significantly associated with CTC levels. For metastatic lung cancers, the presence of the positive lymphoid node was the only factor significantly associated with CTC levels.

Conclusions: We conducted a comprehensive analysis of the tumor properties, radiological features, and genomic characteristics that are significantly associated with CTCs in different lung cancer subtypes. This study helps elucidate the formation mechanism and relevant major regulation molecules of CTCs.

Background: Non-small cell lung cancer (NSCLC) is a significant health concern. The prognostic value of oxidative stress (OS)-related genes in NSCLC remains unclear. The study aimed to explore the prognostic significance of OS-genes in NSCLC using extensive datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO).

Methods: The research used the expression data and clinical information of NSCLC patients to develop a risk-score model. A total of 74 OS-related differentially expressed genes (DEGs) were identified by comparing NSCLC and control samples. Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were employed to identify the prognostic biomarkers. A risk-score model was constructed and validated with receiver operating characteristic (ROC) curves in TCGA and GSE72094 datasets. The model's accuracy was further verified by univariate and multivariate Cox regression.

Results: The identified biomarkers, including lactate dehydrogenase A (LDHA), protein tyrosine phosphatase receptor type N (PTPRN), and transient receptor potential cation channel subfamily A (TRPA1) demonstrated prognostic significance in NSCLC. The risk-score model showed good predictive accuracy, with 1-year area under the curves (AUC) of 0.661, 3-year AUC of 0.648, and 5-year AUC of 0.634 in the TCGA dataset, and 1-year AUC of 0.643, 3-year AUC of 0.648, and 5-year AUC of 0.662 in the GSE72094 dataset. A nomogram integrating risk score and tumor node metastasis (TNM) stage was developed. The signature effectively distinguished between patient responses to immunotherapy. High-risk groups were characterized by an immunosuppressive microenvironment and an increased tumor mutational burden (TMB), marked by a higher incidence of mutations in genes such as TP53, DCP1B, ELN, and MAGI2. Organoid drug sensitivity testing revealed that NSCLC patients with a low-risk score responded better to chemotherapy.

Conclusions: This study successfully developed a robust model for predicting patient prognosis in NSCLC, highlighting the critical prognostic value of OS-genes. These findings hold significant potential to refine treatment strategies, and enhance survival outcomes for NSCLC patients. By enabling a personalized therapeutic approach tailored to individual risk scores, this model may facilitate more precise decisions concerning immunotherapy and chemotherapy, thereby optimizing patient management and treatment efficacy.

Background: Cachexia is observed in around 60% of patients with extensive-stage small cell lung cancer (ES-SCLC) and may play an important role in the development of resistance to immunotherapy. This study aims to evaluate the influence of cachexia on the effectiveness of immunotherapy, develop and assess a deep learning (DL)-based prediction model for cachexia, as well as its prognostic value.

Methods: The analysis encompassed ES-SCLC patients who received the combination of first-line immunotherapy and chemotherapy from Shandong Cancer Hospital and Institute, Qilu Hospital, and Jining First People's Hospital. Survival analysis was conducted to examine the correlation between cachexia and the efficacy of immunotherapy. Medical records and computed tomography (CT) images of the third lumbar vertebra (L3) level were collected to construct the clinical model, radiomics, and DL models. The receiver operating characteristic (ROC) curve analysis was conducted to assess and analyze the efficacy of various models in detecting and evaluating the risk of cachexia.

Results: A total of 231 ES-SCLC patients were enrolled in the study. Cachexia was related to inferior progression-free survival (PFS) and overall survival (OS). In internal and external validation cohorts, the area under the curve (AUC) of the DL model were 0.73 and 0.71. Conversely, the radiomics model in external validation cohort recorded an AUC of 0.67, highlighting the superior performance of the DL model and its demonstrated capability for effective generalization in external validation. All patients were categorized into two groups, namely high risk and low risk using the DL model. It was shown that patients with low-risk cachexia were associated with significantly prolonged PFS and OS.

Conclusions: The DL model not only had better performance in predicting cachexia but also correlated with survival outcomes of ES-SCLC patients who receiving initial immunotherapy.

Background: Radiation-induced lung injury (RILI) is one of the serious adverse reactions of thoracic radiotherapy, which largely limits the dose and therapeutic effect of radiotherapy. The underlying mechanism has not been elucidated. RILI is characterized by an acute inflammatory response, and stimulator of interferon genes (STING) has been reported to play an important role in regulating inflammation and innate immune activation. However, its role in RLLI, remains unclear. Here, we reported the potential therapeutic effect of STING inhibitor H-151 on RILI.

Methods: C57BL/6J mice were exposed to 20 Gy whole-thorax irradiation and H-151 was injected intraperitoneally from the day of irradiation for 4 weeks. The degree of RILI was then assessed. To further explore the mechanism of STING in RILI, the supernatant of irradiated lung epithelial cell MLE-12 was co-cultured with embryonic fibroblast cell NIH/3T3.

Results: The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING pathway is abnormally activated in irradiated mouse lung tissues. The early application of STING inhibitor significantly alleviated radiation-induced inflammatory cell infiltration and pro-inflammatory cytokine release in lung tissue, as well as the degree of fibrosis in the late stage. The amount of double-stranded DNA (dsDNA) in the supernatant of irradiated MLE-12 cells was abnormally increased, and the epithelial-derived dsDNA could promote the transformation of fibroblasts into myofibroblasts. Mechanistically, STING could mediate the activation of fibroblasts to myofibroblasts via the PKR-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) pathway.

Conclusions: Our study focused on the activation of cGAS-STING signaling pathway in RILI, and inhibition of STING significantly ameliorated RILI in mice. STING mediated the effect of radiation-induced dsDNA release to stimulate the activation of inflammatory response, and STING restriction significantly delayed the fibrosis process through the PERK-eIF2α pathway, suggesting that STING intervention may pave a new avenue for the treatment of RILI.

Background: Bone metastasis (BoM) is a prevalent occurrence in patients with non-small cell lung cancer (NSCLC), significantly impacting prognosis and diminishing both survival rates and patients' quality of life. More and more studies have demonstrated that immunotherapy can improve the prognosis of NSCLC patients with bone metastases. Previous investigations pertaining to BoM in NSCLC have generally suffered from small sample sizes, absence of propensity score matching (PSM) to equate baseline characteristics, and an omission of the examination of patterns of treatment failure. This study aims to evaluate the prognostic significance of BoM and potential clinical value of bone radiation in metastatic NSCLC patients receiving immunotherapy.

Methods: Metastatic NSCLC patients receiving programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors from three academic centers were enrolled in a prospective, observational trial (https://clinicaltrials.gov/study/NCT04766515) and those with measurable disease and adequate follow-up were retrospectively reviewed. Propensity score matched (PSM) patients with and without BoM were included in this study. Treatment efficacy, pattern of failure and clinical value of bone radiotherapy were extensively evaluated.

Results: A total of 544 out of 1,451 immunotherapy-treated NSCLC patients were included after PSM, including 272 with BoM and 272 without. Patients with baseline BoM had a median progression-free survival (PFS) of 7.8 months [95% confidence interval (CI): 7.0-8.7], lower than those without it (9.5 months; 95% CI: 8.9-10.0) (P<0.001). Patients with baseline BoM had a median overall survival (OS) of 14.5 months (95% CI: 12.6-16.4), lower than those without 27.6 months (95% CI: 25.1-30.1) (P<0.001). Patients with BoM also had lower objective response rate than those without it (11.1% vs. 15.8%, P<0.001). Initial disease progression in the bone was more common in those with BoM (56.5%) compared to those without it (31.7%) (P<0.001). Meanwhile, among patients with BoM, no significant difference of PFS was found between those receiving bone radiation or not, possibly due to a dominant use of palliative radiotherapy.

Conclusions: Baseline BoM correlated with worse prognosis and palliative bone radiation did not improve PFS in metastatic NSCLC patients receiving PD-1/PD-L1 inhibitors.