Risk factors of immune checkpoint inhibitor-related pneumonitis after neoadjuvant immunochemotherapy for resectable NSCLC.

BACKGROUND: The incidence of checkpoint inhibitor-associated pneumonitis (CIP) in advanced non-small cell lung cancer (NSCLC) has been substantiated through large-scale clinical trials or real-world studies. However, reports on CIP incidence within the context of neoadjuvant immunotherapy for resectable NSCLC remain scarce. This study endeavors to investigate the incidence, risk factors, and outcomes of CIP in patients with resectable NSCLC receiving neoadjuvant immunochemotherapy. METHODS: A retrospective, case-control study was conducted on patients diagnosed with NSCLC stages IIA-IIIB who received neoadjuvant immunochemotherapy between January 2018 and September 2022. Patients were stratified into two groups based on the presence or absence of CIP, facilitating a comparative analysis of clinical characteristics, treatment modalities, physiological indicators, and prognostic outcomes . RESULTS: The study cohort comprised 245 patients, with 11.4% (28/245) experiencing CIP. The median period of CIP onset was 70 (range, 40-221) days. The incidence of severe CIP (grade 3-4) was 3.7% (9/245). Patients with CIP showed a higher all-cause mortality rate of 21.4% (6/28) compared to that of patients without CIP. Those who developed CIP exhibited elevated body mass index (BMI) values (p = 0.028) and increased fibrinogen (FIB) levels (p < 0.001), alongside a significant decrease in both diffusing capacity for carbon monoxide (DLCO)% pred (p = 0.001) and DLCO/VA% pred (p = 0.021) after neoadjuvant therapy compared to pre-indicators. Receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve of three assessed variables (FIB levels, BMI, DLCO) reached 0.806 in predicting CIP occurrence at an early stage. CONCLUSIONS: This cohort demonstrated that elevated BMI, increased FIB levels, and decreased pulmonary diffusion function after neoadjuvant therapy are risk factors of CIP occurrence. Early assessment and continuous monitoring of these indicators are imperative for the predictive identification of CIP, enhancing patient management and outcomes.

Integrated analysis reveals critical cisplatin-resistance regulators E2F7 contributed to tumor progression and metastasis in lung adenocarcinoma.

BACKGROUND: Drug resistance poses a significant challenge in cancer treatment, particularly as a leading cause of therapy failure. Cisplatin, the primary drug for lung adenocarcinoma (LUAD) chemotherapy, shows effective treatment outcomes. However, the development of resistance against cisplatin is a major obstacle. Therefore, identifying genes resistant to cisplatin and adopting personalized treatment could significantly improve patient outcomes. METHODS: By examining transcriptome data of cisplatin-resistant LUAD cells from the GEO database, 181 genes associated with cisplatin resistance were identified. Using univariate regression analysis, random forest and multivariate regression analyses, two prognostic genes, E2F7 and FAM83A, were identified. This study developed a prognostic model utilizing E2F7 and FAM83A as key indicators. The Cell Counting Kit 8 assay, Transwell assay, and flow cytometry were used to detect the effects of E2F7 on the proliferation, migration, invasiveness and apoptosis of A549/PC9 cells. Western blotting was used to determine the effect of E2F7 on AKT/mTOR signaling pathway. RESULTS: This study has pinpointed two crucial genes associated with cisplatin resistance, E2F7 and FAM83A, and developed a comprehensive model to assist in the diagnosis, prognosis, and evaluation of relapse risk in LUAD. Analysis revealed that patients at higher risk, according to these genetic markers, had elevated levels of immune checkpoints (PD-L1 and PD-L2). The prognostic and diagnosis values of E2F7 and FAM83A were further confirmed in clinical data. Furthermore, inhibiting E2F7 in lung cancer cells markedly reduced their proliferation, migration, invasion, and increased apoptosis. In vivo experiments corroborated these findings, showing reduced tumor growth and lung metastasis upon E2F7 suppression in lung cancer models. CONCLUSION: Our study affirms the prognostic value of a model based on two DEGs, offering a reliable method for predicting the success of tumor immunotherapy in patients with LUAD. The diagnostic and predictive model based on these genes demonstrates excellent performance. In vitro, reducing E2F7 levels shows antitumor effects by blocking LUAD growth and progression. Further investigation into the molecular mechanisms has highlighted E2F7's effect on the AKT/mTOR signaling pathway, underscoring its therapeutic potential. In the era of personalized medicine, this DEG-based model promises to guide clinical practice.

Integrase Interactor 1 (INI1) Deficiency in a Lung Cancer Patient Presents Nonresponse to Immunotherapy and Tazemetostat: A Case Report.

Integrase interactor 1 (INI1)-deficient lung cancer is extremely rare, often with poor prognosis, and lacks effective treatment. Previous studies have reported the efficacy of immunotherapy and enhancer of the zeste homolog 2 (EZH2) inhibitor tazemetostat in various types of INI1-deficient tumors, such as sarcomas. However, the effectiveness of these treatments in INI1-deficient lung cancer has not yet been verified. We hereby report a case of a patient who was diagnosed with advanced squamous lung cancer with INI1 deficiency and received chemotherapy, immunotherapy, and tazemetostat treatments successively. The patient showed optimal response in the initial chemotherapy combined with anti-programmed cell death protein 1 (PD-1) immunotherapy, made rapid progress in the subsequent stage of maintenance immunotherapy, and showed nonresponse to tazemetostat. To the best of our knowledge, this is the first case of a lung cancer patient with INI1 deficiency who received tazemetostat treatment.

Targeting immune checkpoints on tumor-associated macrophages in tumor immunotherapy.

Unprecedented breakthroughs have been made in cancer immunotherapy in recent years. Particularly immune checkpoint inhibitors have fostered hope for patients with cancer. However, immunotherapy still exhibits certain limitations, such as a low response rate, limited efficacy in certain populations, and adverse events in certain tumors. Therefore, exploring strategies that can improve clinical response rates in patients is crucial. Tumor-associated macrophages (TAMs) are the predominant immune cells that infiltrate the tumor microenvironment and express a variety of immune checkpoints that impact immune functions. Mounting evidence indicates that immune checkpoints in TAMs are closely associated with the prognosis of patients with tumors receiving immunotherapy. This review centers on the regulatory mechanisms governing immune checkpoint expression in macrophages and strategies aimed at improving immune checkpoint therapies. Our review provides insights into potential therapeutic targets to improve the efficacy of immune checkpoint blockade and key clues to developing novel tumor immunotherapies.