Identification of immune-related gene signature for non-small cell lung cancer patients with immune checkpoint inhibitors.

Background: The utilization of immune checkpoint inhibitors (ICIs) has become the established protocol for treating advanced non-small cell lung cancer (NSCLC). This work aimed to identify the immune-related gene signature that can predict the prognosis of NSCLC patients receiving ICI treatment. Methods: The ImmPort database was queried to obtain a list of immune-related genes (IRGs). Differentially expressed IRGs in NSCLC patients were identified using the TCGA database. RNA-seq data and clinical information from NSCLC patients receiving immunotherapy were obtained from the GEO database (GSE93157 and ////). A gene signature was generated through multivariate Cox and LASSO regression analyses. The prognostic value and function of this gene signature were thoroughly investigated using comprehensive bioinformatics analyses. Results: A total of 6 prognostic-related genes were identified from 617 differentially expressed genes, and two prognostic-related differentially expressed genes (CAMP and IL17A) were determined to construct gene signature. Our gene signature demonstrated superior performance compared to other clinicopathological parameters in predicting the prognosis of NSCLC patients receiving immunotherapy, with an area under the ROC curve (AUC) of 0.812. Furthermore, immune infiltration analysis indicated that the high-risk group was enriched with resting CD4 T cell memory, while the low-risk group showed a "hot" tumor microenvironment that promotes anti-tumor immunity in NSCLC patients. Conclusion: Gene signatures based on immune-related genes exhibited excellent indicator performance of prognosis and immune infiltration, which has the potential to be an effective biomarker for NSCLC with ICI treatment.

Programmable DNA Circuit-Facilitated Determination of Circulating Extracellular Vesicle PD-L1 for Lung Cancer Diagnosis and Immunotherapy Response Prediction.

Circulating extracellular vesicle (EV) PD-L1 is correlated with the occurrence and progression of lung cancer and has great potential as a valuable diagnostic and immunotherapy predictive biomarker. In this work, we propose a fluorescent biosensing method for the sensitive and accurate determination of circulating EV PD-L1. Specifically, after the phosphatidylserine-targeting peptide-assisted magnetic enrichment, a programmable DNA circuit is designed to translate the presence of PD-L1 to the appearance of numerous duplex DNA probes on the circulating EV surface. Upon fructose treatment, these newly formed duplex DNA probes are released from the EV surface to activate the trans-cleavage activity of CRISPR/Cas12a system, which finally produces a significant fluorescence signal. Experimental results reveal that the method not only enables sensitive determination of EV PD-L1 with a detection limit of 67 particles/mL but also demonstrates the potential use in the diagnosis and immunotherapy response prediction of lung cancer in a principle-of-proof study. Therefore, the method may provide a useful tool for EV PD-L1 determination, which may provide valuable information for the precise diagnosis and personalized treatment of lung cancer patients.

Immunotherapy resistance of lung cancer.

In recent years, immunotherapy has made remarkable breakthroughs and brought long-term survival benefits to lung cancer patients. However, a high percentage of patients do not respond to immunotherapy or their responses are transient, indicating the existence of immune resistance. Current studies show that the interactions between cancer cells and immune system are continuous and dynamic. A range of cancer cell-autonomous characteristics, tumor microenvironment factors, and host-related influences account for heterogenous responses. Furthermore, with the identification of new targets of immunotherapy and the development of immune-based combinations, we propose the response strategies to overcome resistance.

Treatment of small cell lung cancer: recent advances.

PURPOSE OF REVIEW: In this article, we aimed to summarize the recent progress being made in treatment of small cell lung cancer (SCLC). RECENT FINDINGS: SCLC is characterized by strong invasiveness, easy recurrence and early metastasis. In recent years, the emergence of immune checkpoint inhibitors (ICIs) therapy has broken the deadlock in the treatment field of SCLC. Combination strategies, such as the addition of ICIs to chemotherapy and radiotherapy, are actively underway. Some of these strategies have yielded significant survival benefits and tolerable adverse events, whereas several of them have failed with no significant improvement. In addition, the new classification of SCLC based on genomic analysis has deepened the understanding of SCLC and suggested new therapeutic directions. Similarly, the discovery of some new therapeutic targets, such as DDL3, CDK7 and PARP, also brings new hope for improving the survival of patients with SCLC. SUMMARY: In this article, we will review the recent advances of therapeutic regimen for patients with SCLC. Following the revolutionary success of adding ICIs to chemotherapy, more varieties of combination strategies have been explored in recent trials. In addition, therapeutic drug research and efficacy evaluation against for new targets are under investigation. Altogether, progress on genomic analysis, investigation of biological pathways and treatment regimen combination are providing renewed hope for patients with SCLC.

Treatment efficacy of HER2-mutant lung adenocarcinoma by immune checkpoint inhibitors: a multicenter retrospective study.

BACKGROUND: Despite the remarkable clinical advance of immune checkpoint inhibitors (ICIs) in the treatment of lung cancer, there are limited studies focused on evaluating efficacy of ICIs for patients with human epidermal growth factor receptor 2 (HER2)-mutant lung adenocarcinoma. METHODS: We conducted a multicenter retrospective study of patients with HER2-mutant lung adenocarcinoma who received ICIs therapy at Shanghai Pulmonary Hospital, Shanghai Chest Hospital and the First Affiliated Hospital of Wenzhou Medical University between 2016 and 2021. Response was defined with reference to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: Among the 26 patients enrolled in our study, the overall objective response rate (ORR) was 38.5%, disease control rate (DCR) was 84.6% and median progression-free survival (PFS) was 7.4 months. Majority of patients were treated with immunochemotherapy combination regimens (16/26, 61.5%), with a median PFS of 8.4 months. Among the 9 patients receiving ICIs-based therapy as first-line treatment, 5 patients had partial response (PR) and 4 patients had stable disease (SD), with a median PFS of 9.1 months. Of the entire cohort, 5 patients who received ICIs before epidermal growth factor receptor (EGFR)/HER2-targeting drugs achieved a median PFS of 8.4 months. CONCLUSION: Our retrospective study provides clinical evidence that front line of ICIs-based therapy is also worth considering for the treatment to improve survival outcomes of patients with HER2-mutant lung adenocarcinoma.

Real-world outcomes of chemo-antiangiogenesis versus chemo-immunotherapy combinations in EGFR-mutant advanced non-small cell lung cancer patients after failure of EGFR-TKI therapy.

BACKGROUND: Despite the potent efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC) patients, drug resistance inevitably ensues, and there remains a paucity of treatment options in clinical practice. METHODS: We identified patients with EGFR-mutant advanced NSCLC presenting to Shanghai Pulmonary Hospital and Shanghai Chest Hospital between January 2015 and December 2020 treated with chemo-antiangiogenesis or chemo-immunotherapy combinations after EGFR-TKI resistance. Patient information was collected, and the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) were assessed. RESULTS: A total of 144 patients who met our inclusion criteria were enrolled. Chemo-immunotherapy combinations achieved a higher objective response rate (ORR) compared with chemo-antiangiogenesis combinations (29.5% vs. 13.0%, P=0.018). The DCR was similar between the two groups (93.0% vs. 88.6%, P=0.585), as was the median PFS (7.59 vs. 6.90 months, P=0.552). In the subgroup analyses, patients who developed secondary T790M mutations after EGFR-TKI treatment were less likely to benefit from chemo-immunotherapy combinations than their T790M-negative counterparts (3.42 vs. 7.63 months, P=0.028). For patients who received chemo-antiangiogenesis combinations after TKI resistance, no significant difference was observed in the median PFS between T790M-positive and T790M-negative patients (median PFS: 5.33 vs. 7.46 months, P=0.202). Additionally, multivariate analysis showed that an elevated platelet count was independently associated with a worse PFS for both groups. CONCLUSIONS: The efficacy of chemo-immunotherapy combinations was comparable to chemo-antiangiogenesis combinations after failure of EGFR-TKI therapy. For patients harboring EGFR T790M mutations, chemo-antiangiogenesis combinations may be the preferred therapeutic option. In addition, platelet count could be a potential prognostic factor for patients after failure of EGFR-TKI therapy. Further research should be conducted on larger populations and in a prospective setting.

Favorable clinical outcomes of checkpoint inhibitor-based combinations after progression with immunotherapy in advanced non-small cell lung cancer.

Aim: Immune checkpoint inhibitors (ICIs) have dramatically changed the treatment paradigm in patients with non-small-cell lung cancer (NSCLC). However, progression patterns with immunotherapy are currently unclear and therapeutic options beyond resistance remain challenging. Methods: We reviewed advanced NSCLC patients between January 2016 and December 2019 who were treated with anti-PD-1/PD-L1 inhibitors in our center and identified those who developed disease progression. Later-line treatment strategies were collected and objective response rate, progression-free survival (PFS), and overall survival (OS) were assessed. Results: Of the 118 patients, 46 (39.0%) showed oligoprogression and 72 (61.0%) showed systemic progression. No difference in progression patterns was observed between monotherapy and combination therapy. Systemic progression was strongly associated with never-smokers (51.4% vs. 21.7%, P = 0.001) and ECOG PS = 2 (13.9% vs. 2.2%, P = 0.048) at baseline. The distribution of progression sites was roughly similar between oligoprogression and systemic progression, and the most commonly affected anatomic site was lung (66.9%), followed by bone (12.7%) and lymph nodes (11.0%). For patients beyond first disease progression, checkpoint inhibitor-based combinations could lead to a significantly longer PFS2 compared with ICIs monotherapy (9.63 months vs. 4.23 months, P = 0.004, HR = 0.394, 95%CI: 0.174-0.893) and other therapy (9.63 months vs. 4.07 months, P = 0.046, HR = 0.565, 95%CI: 0.326-0.980). Median OS of the ICIs combination group was not reached but was significantly longer than other therapy group (NR vs. 14.37 months, P = 0.010, HR = 0.332, 95%CI: 0.167-0.661). Conclusion: Systemic progression occurs more frequently among NSCLC patients receiving ICIs. Checkpoint inhibitor-based combinations show favorable outcomes as subsequent treatment strategies after the failure of previous ICIs treatment.

Immunohistochemistry and clinical value of sirtuin 2 in non-metastasized non-small cell lung cancer.

BACKGROUND: This study aimed to define whether sirtuin 2 (SIRT2) expression levels are related to the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: A survival analysis was carried out using the Kaplan-Meier (KM) plotter database. Immunohistochemical staining was performed and KM's method was used to estimate the survival rates for SIRT2 expression in 72 clinical samples. RESULTS: A survival analysis of 1,926 NSCLC patients showed that patients with low SIRT2 expression levels had significantly longer overall survival (OS) than those with high SIRT2 expression levels (P=0.0077; HR =1.19). In 72 non-metastasized NSCLC tissues, the positive rate of SIRT2 expression was 90.3% (65/72), among which, the positive expression rates of squamous cell carcinoma (SCC) and adenocarcinoma (ADC) were 96.4% (27/28) and 85.4% (35/41), respectively. Survival analysis showed that patients with low SIRT2 expression levels had significantly longer median survival time (MST) than those with high SIRT2 expression levels (15.0 versus 14.0 months, P=0.029). Furthermore, the results of subgroup analysis demonstrated patients with low SIRT2 expression levels had significantly longer survival time in ADC group (15.0 versus 12.0 months, P=0.022), but there wasn't significant difference in SCC group (15.0 versus 14.0 months, P=0.932). A multivariate Cox proportional hazards model, which included gender, age, TNM stage, differentiation and SIRT2 expression, showed that SIRT2 expression was an independent factor related to prognosis [HR =1.903, 95% confidence interval (95% CI): 1.085-3.339, P=0.025]. CONCLUSIONS: SIRT2 expression levels were significantly related to the survival time of patients with lung ADC but not SCC. Our study indicated SIRT2 was perhaps a specific prognostic biomarker for non-metastasized lung ADC.

SPOP promotes FADD degradation and inhibits NF-κB activity in non-small cell lung cancer.

FAS-associated protein with death domain (FADD) is the pivotal adaptor protein, which transmits apoptotic signals mediated by the death receptors. Here we report that high FADD protein level predicts poor prognosis of non-small cell lung cancer (NSCLC) patients and its protein level is mainly regulated by the 26S proteasome. We also found that ubiquitin ligase SPOP (speckle-type POZ protein) binds to FADD and mediates its degradation, which can be blocked by MG132 treatment. Notably, SPOP inhibits NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity and its target genes expression via FADD. These results reveal the function of SPOP-FADDNFκB axis in NSCLC cells, which is associated with prognosis of NSCLC patients.