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Immune checkpoint inhibitor related pneumonitis is a serious adverse reaction with diverse clinical and radiologic patterns, which make both diagnosis and treatment challenging. Therefore, understanding its underlying biology is crucial for improving clinical management. Bronchoalveolar lavage fluid provides a minimally invasive way to explore the lung immune environment, and it supports cytologic, molecular, and multi-omics analyses. In particular, BALF lymphocytosis serves as a key diagnostic sign. Furthermore, single-cell sequencing has revealed that abnormal T-cell activation and myeloid cell reprogramming play central roles in the development of CIP. These findings have, in turn, led to the identification of potential biomarkers such as CCL18, IL-6, and IP-10 for early detection and disease monitoring. However, the absence of standardized sampling and interpretation methods still limits the reproducibility of results and the broader application of BALF analysis in clinical practice. In the future, integrating BALF-derived data into artificial intelligence frameworks may enhance diagnostic precision and guide personalized therapy. Overall, BALF represents a valuable platform for refining CIP classification, clarifying disease mechanisms, and supporting the development of targeted treatments.

Immune checkpoint inhibitors (ICIs) have become a high-profile regimen for malignancy recently. However, only a small subpopulation obtains long-term clinical benefit. How to select optimal patients by reasonable biomarkers remains a hot topic. Paired tissue samples and blood samples from 51 patients with advanced malignancies were collected for correlation analysis. Dynamic changes in blood PD-L1 (bPD-L1) expression, including PD-L1 mRNA, exosomal PD-L1 (exoPD-L1) protein and soluble PD-L1 (sPD-L1), were detected after 2 months of ICIs treatment in advanced non-small-cell lung cancer (NSCLC) patients. The best cutoff values for progression-free survival (PFS) and overall survival (OS) of all three biomarkers were calculated with R software. In 51 cases of various malignancies, those with positive tissue PD-L1 (tPD-L1) had significantly higher PD-L1 mRNA than those with negative tPD-L1. In 40 advanced NSCLC patients, those with a fold change of PD-L1 mRNA ≥ 2.04 had better PFS, OS and best objective response (bOR) rate. In addition, a fold change of exoPD-L1 ≥ 1.86 was also found to be associated with better efficacy and OS in a cohort of 21 advanced NSCLC cases. The dynamic change of sPD-L1 was not associated with efficacy and OS. Furthermore, the combination of PD-L1 mRNA and exoPD-L1 could screen better patients for potential benefit from ICIs treatment. There was a positive correlation between bPD-L1 and tPD-L1 expression. Increased expression of PD-L1 mRNA, exoPD-L1, or both in early stage of ICIs treatment could serve as positive biomarkers of efficacy and OS in advanced NSCLC patients.

Background and objectives Immune checkpoint inhibitors (ICIs) bring cancer patients tumor control and survival benefits, yet they also trigger immune-related adverse effects (irAEs), notably checkpoint inhibitor-related pneumonitis (CIP), affecting about 5% of patients among whom 1–2% experiencing severe grade 3 or higher pneumonitis. Current research points to potential links with T cell subset dysfunction and autoantibody increase, but the specific mechanisms underlying different grades of CIP are understudied. Methods Herein, we employed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid (BALF) from CIP patients across varying severity levels, aiming to elucidate underlying immune environment and mechanisms of CIP progression at cellular and molecular levels. Findings Totally, 121,409 high qualified cells from BALF of 11 patients were annotated and categorized into five major cell types. Severe CIP (CIP-S) cases have a significant increase in the percentage of unreported epithelial cells in their bronchoalveolar lavage fluid compared with mild CIP (CIP-M) cases. These cells were defined as aberrant basaloid cells. They upregulated SOX9, increased the expression of CXCL3/5, recruited neutrophils, and activated the immune system. Additionally, macrophages in the CIP-S group had stronger antigen-presenting abilities and resulted in more CD8 + effective T cells infiltrated. Conclusions Utilizing single-cell sequencing of BALF, we discovered an enriched population of aberrant basaloid cells in CIP-S patients, which had not been previously reported. Aberrant basaloid cells may upregulate SOX9 via CXCL3/5-CXCR2 to recruit and activate neutrophils, and further activate the immune system, resulting in CIP-S. This finding could identify new targets for stratified treatment of CIP patients, holding promise of a novel approach for clinical guidance.

The evolutionary dynamics of tumor‐associated neoantigens carry information about drug sensitivity and resistance to the immune checkpoint blockade (ICB). However, the spectrum of somatic mutations is highly heterogeneous among patients, making it difficult to track neoantigens by circulating tumor DNA (ctDNA) sequencing using “one size fits all” commercial gene panels. Thus, individually customized panels (ICPs) are needed to track neoantigen evolution comprehensively during ICB treatment. Dominant neoantigens are predicted from whole exome sequencing data for treatment‐naïve tumor tissues. Panels targeting predicted neoantigens are used for personalized ctDNA sequencing. Analyzing ten patients with non‐small cell lung cancer, ICPs are effective for tracking most predicted dominant neoantigens (80–100%) in serial peripheral blood samples, and to detect substantially more genes (18–30) than the capacity of current commercial gene panels. A more than 50% decrease in ctDNA concentration after eight weeks of ICB administration is associated with favorable progression‐free survival. Furthermore, at the individual level, the magnitude of the early ctDNA response is correlated with the subsequent change in tumor burden. The application of ICP‐based ctDNA sequencing is expected to improve the understanding of ICB‐driven tumor evolution and to provide personalized management strategies that optimize the clinical benefits of immunotherapies. Inter‐individual heterogeneity of mutation profiling is the primary obstacle in effective in vivo monitoring of mutation‐directed T‐cell killing using ctDNA sequencing. Herein, a customized sequencing strategy is developed that mainly targets predicted neoantigen‐coding mutations. This approach broadens the ctDNA sequencing coverage and is expected to improve personalized management strategies that optimize the clinical benefits from checkpoint immunotherapies.

The prognosis of non-small cell lung cancer (NSCLC) is poor, particularly for patients with metastatic disease. Numerous efforts have been made to improve the prognosis of these patients; however, only a small number of studies have explored the occurrence rate and prognostic value of different patterns of distant metastasis (DM) in NSCLC systematically. To investigate these, information from patients diagnosed with NSCLC between 2010 and 2014 was collected from the Surveillance, Epidemiology and End Results database. Survival rate comparisons were performed using Kaplan-Meier analysis and log-rank tests. A Cox proportional hazard model was established to determine factors associated with improved overall survival (OS) and cancer-specific survival (CSS). The present study revealed that the most common site of single metastasis occurrence was bone, and the least common was the liver for NSCLC. As for multi-site metastases, the most common two-site metastasis involved bone and lung, and the most common three-site metastasis involved bone, liver and lung. As for NSCLC subtypes, large cell carcinoma (LCC) exhibited more specific metastatic features. The most common single metastatic site was the brain for patients with LCC, and the most common two-site metastatic combination was bone and liver. Patients with isolated liver metastasis exhibited the worst OS and CSS among patients with single metastasis. Furthermore, for patients with multi-site metastases, metastases involving the liver were associated with the worst OS and CSS among various combinations. To the best of our knowledge, the present study is the first to investigate the occurrence rate and prognostic value of different metastatic patterns of site-specific DM for NSCLC using a large population-based dataset. The findings of the present study may have vital implications for classifying patients with advanced NSCLC, thus laying a foundation for individualized precise treatment.

Background The study was conducted to compare the clinicopathological characteristics, survival outcomes, and metastatic patterns between pulmonary large cell neuroendocrine carcinoma (LCNEC) and other non‐small cell lung cancer (ONSCLC), and to identify the prognostic factors of LCNEC. Methods Data of patients diagnosed with LCNEC and ONSCLC from 2004 to 2014 were obtained from the Surveillance, Epidemiology, and End Results dataset. Pearson’s chi‐square tests were used to compare differences in clinicopathological characteristics. The Kaplan–Meier method was used for survival analysis. A propensity score was used for matching and a Cox proportional hazards model was used for multivariate and subgroup analyses. Results A total of 2368 LCNEC cases and 231 672 ONSCLC cases were identified. LCNEC incidence increased slightly over time. Except for marital status, LCNEC patients had obviously different biological features to ONSCLC patients. Survival analysis showed that LCNEC had poorer outcomes than ONSCLC. Multivariate analysis revealed that female gender, black race, surgery, radiation, and chemotherapy were protective factors for LCNEC. Matched subgroup analysis further demonstrated that most subgroup factors favored ONSCLC, especially in early stage. Early‐stage LCNEC patients had a higher risk of lung cancer‐specific death than early‐stage ONSCLC patients. Moreover, metastatic patterns were different between LCNEC and ONSCLC. LCNEC patients with isolated liver metastasis or combined invasion to other organs had poorer survival rates. Conclusions LCNEC has totally different clinicopathological characteristics and metastatic patterns to ONSCLC. LCNEC also has poorer survival outcomes, primarily because of isolated liver metastasis or combined invasion to other organs. Most subgroup factors are adverse factors for LCNEC.

A new progression pattern, hyperprogressive disease (HPD), has been recently acknowledged in cancer patients accepted immune checkpoint inhibitors (ICIs). We report a unique case of cervical small cell carcinoma which showed primary resistance to pembrolizumab and was with a rapid radiological progression after the initiate of ICIs treatment. However, the detection results of multiple predictive biomarkers suggested that the patient was eligible for ICIs treatment. The whole exome sequencing showed that AKT1 E17K mutation was high (26.316%) in tumor tissue, and dynamic monitoring of circulating tumor DNA indicated that AKT1 E17K mutation rate was increasing successively and highly consistent with tumor growth in peripheral blood. Therefore, the correlation between AKT1 E17K mutation and HPD, and the role of AKT1 E17K mutation in identifying patients who might not benefit from ICIs treatment need to be further studied. Keywords: hyperprogressive disease, cervical small cell carcinoma, immune checkpoint inhibitor

Objectives Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) has significant therapeutic efficacy in non‐small‐cell lung cancer (NSCLC) patients. However, acquired resistance is inevitable and limits the long‐term efficacy of EGFR‐TKI. Our study aimed to investigate the role of ras‐associated binding protein 25 (Rab25) in mediating EGFR‐TKI resistance in NSCLC. Materials and Methods Rab25 expression in NSCLC patients was measured by immunohistochemical staining. Western blotting was used to analyse the expression of molecules in the Rab25, EGFR and Wnt signalling pathways. Lentiviral vectors were constructed to knock in and knock out Rab25. The biological function of Rab25 was demonstrated by cell‐counting kit‐8 and flow cytometry. The interaction between Rab25 and β1 integrin was confirmed by co‐immunoprecipitation. Results Rab25 overexpression induced erlotinib resistance, whereas Rab25 knockdown reversed this refractoriness in vitro and in vivo. Moreover, Rab25 interacts with β1 integrin and promotes its trafficking to the cytoplasmic membrane. The membrane‐β1 integrin induced protein kinase B (AKT) phosphorylation and subsequently activated the Wnt/β‐catenin signalling pathway, promoting cell proliferation. Furthermore, high Rab25 expression was associated with poor response to EGFR‐TKI treatment in NSCLC patients. Conclusions Rab25 mediates erlotinib resistance by activating the β1 integrin/AKT/β‐catenin signalling pathway. Rab25 may be a predictive biomarker and has potential therapeutic value in NSCLC patients with acquired resistance to EGFR‐TKI.

Myeloid‐derived suppressor cells (MDSCs) play a pivotal role in establishing an immunosuppressive tumor microenvironment (TME), yet the mechanisms underlying their functional activation remain incompletely defined. Here, we identify the Fgl2‐FcγRIIB signaling axis as a critical mediator of MDSC‐driven immune evasion across solid tumors. Analysis of clinical specimens revealed that Fgl2 expression is significantly elevated in tumor tissues and inversely correlates with CD8 + T cell infiltration, while positively associating with the accumulation of FcγRIIB + MDSCs and poor patient prognosis. We demonstrate that tumor‐derived exosomes (TEX) function as efficient carriers that deliver membrane‐bound Fgl2 (mFgl2) to MDSCs. These exosomes are internalized by MDSCs through FcγRIIB‐mediated endocytosis, leading to an enhanced immunosuppressive function characterized by upregulated arginase‐1 (Arg‐1) and inducible nitric oxide synthase (iNOS) expression and an increased capacity to suppress CD8 + T cell proliferation. Genetic ablation of FcγRIIB or antibody‐mediated neutralization of Fgl2 abolished this exosome‐mediated immunosuppressive programming, restoring T cell activity and impairing tumor growth in vivo. Importantly, a therapeutic strategy combining an exosome secretion inhibitor, in combination with PD‐L1 blockade and MDSCs depletion, synergistically achieved potent antitumor effects. Our findings unveil a novel exosome‐dependent mechanism through which tumors systemically educate MDSCs, establishing the Fgl2‐FcγRIIB axis as a promising broad‐spectrum target for cancer immunotherapy.

Inter‐individual heterogeneity of the mutational spectrum is the major obstacle of effective in vivo monitoring of mutation‐directed T cell killing by ctDNA sequencing. In article number 1903410, Jianguo Sun, Bo Zhu, and co‐workers develop a customized sequencing strategy that mainly targets predicted neoantigen‐coding mutations. This work significantly broadens the coverage of ctDNA sequencing and is expected to improve personalized management strategies optimizing the clinical benefits of checkpoint immunotherapies.