Translational lung cancer research最新文献

{"title":"Patient-focused insights: how emotional distress shapes immunotherapy response in non-small cell lung cancer.","authors":"Federica Pecci, Paolo Tarantino","doi":"10.21037/tlcr-24-904","DOIUrl":"https://doi.org/10.21037/tlcr-24-904","url":null,"abstract":"","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3819-3823"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative peripheral live single T-cell dynamic polyfunctionality profiling predicts lung cancer checkpoint immunotherapy treatment response and clinical outcomes.","authors":"Zuan-Fu Lim, Xiaoliang Wu, Lin Zhu, Heidar Albandar, Maria Hafez, Chenchen Zhao, Mohammed Almubarak, Matthew Smolkin, Hong Zheng, Sijin Wen, Patrick C Ma","doi":"10.21037/tlcr-24-260","DOIUrl":"https://doi.org/10.21037/tlcr-24-260","url":null,"abstract":"<p><strong>Background: </strong>Predictive biomarkers for immune checkpoint inhibitors (ICIs), e.g., programmed death ligand-1 (PD-L1) tumor proportional score (TPS), remain limited in clinical applications. Predictive biomarkers that require invasive tumor biopsy procedures are practically challenging especially when longitudinal follow-up is required. Clinical utility of tissue-based PD-L1 TPS also becomes diluted when ICI is combined with chemotherapies. Peripheral single T-cell dynamic polyfunctionality profiling offers the opportunity to reveal rare T-cell subpopulations that are polyfunctional and responsible for the underlying ICI treatment molecular response that bulk biological assays cannot achieve. Here, we evaluated a novel live single-cell functional liquid biopsy cytokine profiling platform, IsoLight, as a potential predictive biomarker to track ICI treatment response and clinical outcomes in non-small cell lung cancer (NSCLC).</p><p><strong>Methods: </strong>Peripheral blood mononuclear cell samples of 10 healthy donors and 10 NSCLC patients undergoing ICI-based therapies were collected longitudinally pre-/post-ICI treatment after ≥2 cycles under institutional review board (IRB)-approved protocols. Cancer blood samples were collected from unresectable advanced stage (III-IV) NSCLC patients. Clinical course and treatment response and survival outcomes were extracted from electronic health records, with treatment response assessed by treating oncologists based on RECIST. CD4<sup>+</sup> and CD8<sup>+</sup> T-cells were enriched magnetically and analyzed on the IsoLight platform. Single T-cells were captured in microchambers on IsoCode chips for proteomic immune cytokines profiling. Functional polyfunctionality data from 55,775 single cells were analyzed with IsoSpeak software, 2D- and 3D-t-distributed stochastic neighbor embedding (t-SNE) analysis, kappa coefficient, and Kaplan-Meier survival plots. P values ≤0.05 is considered statistically significant.</p><p><strong>Results: </strong>Pre-treatment baseline polyfunctionality profiles could not differentiate NSCLC patients from healthy subjects, and could not differentiate ICI responders from non-responders. We found a statistically significant difference between responders and non-responders in CD8<sup>+</sup> T-cells' changes in overall polyfunctionality (ΔPolyFx) (P=0.01) and polyfunctional strength index (ΔPSI) (P=0.006) in our dynamic pre-/post-treatment single cell measurements, both performing better than PD-L1 TPS alone (P=0.08). In the 3D-t-SNE analysis, subpopulations of post-treatment CD8<sup>+</sup> T-cells in ICI responders displayed distinct immune cytokine profiles from those in pre-treatment cells. CD8<sup>+</sup> T-cells ΔPolyFx and ΔPSI scores performed better than PD-L1 TPS in ICI response correlation. Moreover, combined PD-L1 strong TPS and ΔPSI >15 scores strongly correlated with early ICI response with a robust kappa coefficient of 1.0 (P=0.003), which was previ","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3323-3343"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term survival after combination therapy with atezolizumab in a patient with small-cell lung cancer: a case report.","authors":"Guangbin Gao, Yajing Wu, Qing Liu, Chang Zhai, Yusuke Inoue, Xinyuan Zhang, Xiaoyan Lv, Wei Zhang, Jun Wang","doi":"10.21037/tlcr-24-981","DOIUrl":"https://doi.org/10.21037/tlcr-24-981","url":null,"abstract":"<p><strong>Background: </strong>Small-cell lung cancer (SCLC) is highly malignant. Despite being highly sensitive to initial chemotherapy and radiotherapy, the recurrence rate is high. Atezolizumab is the first immune checkpoint inhibitor (ICI) that has been proven to provide an overall survival (OS) benefit for extensive-stage SCLC (ES-SCLC), making ICIs in combination with chemotherapy the standard first-line treatment for ES-SCLC. However, the real-world treatment of SCLC is more complex, and multimodal therapy may be needed to achieve long-term patient survival. Few reports on later-line chemotherapy combined with immunotherapy have been published thus far. Moreover, there is limited data on the efficacy and safety of thoracic radiotherapy and radiotherapy for metastatic lesions after multiple lines of treatment have failed in ES-SCLC, and the value of small-molecule antiangiogenesis combined with immunotherapy also needs further exploration.</p><p><strong>Case description: </strong>A patient was diagnosed with mediastinal limited-stage SCLC (LS-SCLC) and experienced local progression following standard chemoradiotherapy and prophylactic cranial irradiation. Subsequently, the patient underwent second-line irinotecan chemotherapy, which resulted in severe hematological toxicity. Upon initiation of third-line therapy with anlotinib, the disease remained stable for 9 months. Unfortunately, imaging revealed the presence of a new lesion at the right lung apex. Nevertheless, there was renewed hope for survival when atezolizumab was introduced as part of the treatment regimen. Despite the later development of brain metastases and metastasis adjacent to the aortic arch, long-term survival was achieved through combination therapy involving immunotherapy, antiangiogenic therapy, and radiotherapy targeting the metastatic lesions. By March 2024, the OS had reached 70 months, with a duration of treatment with atezolizumab of 48 months, and only grade II hypothyroidism occurred during treatment, with no other immunotherapy-related adverse events being observed.</p><p><strong>Conclusions: </strong>This case report suggests the potential efficacy and safety of integrating chemotherapy, immunotherapy, radiotherapy, and antiangiogenic therapy for the treatment of SCLC. Further clinical trials are warranted to validate the value of combining chemotherapy, immunotherapy, radiotherapy, and antiangiogenic therapy.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3795-3806"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of miR-9-3p facilitates ferroptosis by activating SAT1/p53 pathway in lung adenocarcinoma.","authors":"Anqi Wu, Anping Zhang, Tianyi Wang, Jianle Chen, Jiahai Shi","doi":"10.21037/tlcr-24-762","DOIUrl":"10.21037/tlcr-24-762","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and accounts for about 40% of all lung cancer cases. This research aims to investigate the effects of miR-9-3p on ferroptosis in LUAD cells and to elucidate its regulatory mechanisms. Studies have shown that LUAD is related to ferroptosis, and specific microRNAs (miRNA) are also related to ferroptosis. However, further research is needed to elucidate the mechanisms by which miR-9-3p induces ferroptosis in LUAD.</p><p><strong>Methods: </strong>Our study comprehensively analyzed multiple databases to investigate miR-9-3p expression in LUAD tissues. Quantitative polymerase chain reaction (qPCR) was utilized to detect miR-9-3p levels in LUAD cells and tissues, examining its prognostic significance. Reactive oxygen species (ROS) and superoxide dismutase (SOD) assays assessed the impact of miR-9-3p on lipid peroxidation in LUAD cells. Dual-luciferase reporter assays were conducted to evaluate the binding affinity between miR-9-3p and target genes, while Western blotting and immunofluorescence were used to examine the regulation of miR-9-3p on downstream signaling pathways.</p><p><strong>Results: </strong>We observed that miR-9-3p was upregulated in LUAD cells by qPCR, and the ferroptosis of LUAD cells increased upon treatment with erastin following the transfection of miR-9-3p inhibitor. Cell Counting Kit-8 (CCK-8), ROS, and SOD activity assays confirmed that inhibiting miR-9-3p enhanced lipid peroxidation in LUAD cells, contributing to higher rates of ferroptosis. Subsequent dual-luciferase reporter assays validated spermidine/spermine N1-acetyltransferase 1 (SAT1) as a target gene of miR-9-3p. Further Western blot confirmed that miR-9-3p regulated the expression of SAT1 and p53 proteins in p53 wild-type (WT) LUAD cells. Rescue experiments demonstrated that SAT1 was necessary for miR-9-3p to promote cell proliferation and suppress ferroptosis in p53 WT LUAD cells. Additionally, the effect of miR-9-3p on ferroptosis in LUAD cells was regulated by p53 signaling pathway.</p><p><strong>Conclusions: </strong>Overall, these findings demonstrate that miR-9-3p negatively regulates ferroptosis in LUAD cells through SAT1 and p53 signaling pathway, suggesting that miR-9-3p plays a crucial role in LUAD pathogenesis and targeting this miRNA with an inhibitor exhibits promising potential for the treatment of LUAD.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3426-3442"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of artificial intelligence for detecting operable lung cancer on chest radiographs.","authors":"Hyun Joo Shin, Se Hyun Kwak, Kyeong Yeon Kim, Na Young Kim, Kyungsun Nam, Young Jin Kim, Eun-Kyung Kim, Young Joo Suh, Eun Hye Lee","doi":"10.21037/tlcr-24-745","DOIUrl":"https://doi.org/10.21037/tlcr-24-745","url":null,"abstract":"<p><strong>Background: </strong>Despite the importance of early diagnosis of lung cancer and wide availability of chest radiography, the detection of operable stage lung cancer on chest radiographs (CXRs) remains challenging. This study aimed to investigate the effectiveness of artificial intelligence (AI)-based CXR analysis for detecting operable lung cancers.</p><p><strong>Methods: </strong>Patients who underwent lung cancer surgery at two referral hospitals between March 2020 and February 2021 were retrospectively included in this study. Preoperative CXRs of the patients were analyzed using commercial AI-based lesion detection software, and the results of lesion location and types obtained using the software were reviewed by radiologists and pulmonologists, with computed tomography (CT) as a reference standard for determining nodule characteristics. Factors influencing AI detection of lung cancer on CXR were assessed using logistic regression analysis.</p><p><strong>Results: </strong>Among the 594 patients who underwent surgery for lung cancer (median age: 65 years, 51.3% male), the sensitivity of AI for detecting lung cancer on CXR was 57.7%, and it identified 86% of CXR-visible lung cancers. Detection rates of lung cancer by AI increased according to the disease stage: 42.5% for stage IA, 86.3% for stage IB, and 90.9% for stages II-III. The detection rate increased to over 60% from stage IA2 onwards when tumor size exceeded 1 cm. Regarding lesion type on CT, 8.3%, 46.8%, and 77.3% of non-solid, part-solid, and solid nodules, respectively, were detected by AI. Multivariable analysis showed that nodule location in the upper zone [odds ratio (OR) 2.78, P<0.001], peripheral region (OR 4.59, P<0.001), and solid lesion diameter (OR 1.20, P<0.001) were significantly associated with AI detection of lung cancer.</p><p><strong>Conclusions: </strong>AI could be an effective tool for detecting operable lung cancer on CXRs, particularly when lesions are larger and located in the upper and peripheral regions.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3473-3485"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A potential central nervous system niche for trastuzumab deruxtecan in patients with HER2-expressing non-small cell lung cancer.","authors":"Anna-Maria Lazaratos, David J H Bian, Kevin Petrecca, Marie-Christine Guiot, Matthew Dankner","doi":"10.21037/tlcr-24-856","DOIUrl":"https://doi.org/10.21037/tlcr-24-856","url":null,"abstract":"","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3824-3830"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A prognostic nomogram of non-small cell lung cancer based on tumor marker inflammatory nutrition score.","authors":"Yan Feng, Han Qiao, Xiaolei Han, Huaping Tang","doi":"10.21037/tlcr-24-708","DOIUrl":"https://doi.org/10.21037/tlcr-24-708","url":null,"abstract":"<p><strong>Background: </strong>Patients diagnosed with non-small cell lung cancer (NSCLC) usually have a poor prognosis, so it is critical to identify effective biomarkers for prognosis prediction. The aim of this study is to establish a nomogram to evaluate the prognostic significance of blood markers in patients with NSCLC and provide reference for clinical work.</p><p><strong>Methods: </strong>A total of 486 patients with NSCLC who were admitted to hospital from January 2009 to December 2019 were retrospectively analyzed. The cohort was divided into a training set (n=340) and a validation set (n=146). Eleven blood indicators were selected as prognostic parameters by the least absolute shrinkage and selection operator (LASSO) model to establish tumor marker inflammatory nutrition (TMIN) score. Univariate and multivariate regression analyses were performed to establish a TMIN-nomogram model for predicting overall survival (OS) and progression-free survival (PFS). Receiver operating characteristic (ROC) survival curve, calibration curve and clinical decision curve analysis (DCA) were used to evaluate the predictive performance of the TMIN-nomogram model.</p><p><strong>Results: </strong>The TMIN score were constructed for 11 of the most valuable prognostic variables, including white blood cells (WBCs), neutrophils (N), platelets (PLT), albumin (ALB), globulin (GLB), prealbumin (PAB), carcinoembryonic antigen (CEA), cytokeratin fragment 21-1 (CYFRA21-1), fibrinogen (FIB), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR), and patients were divided into low-risk and high-risk groups using optimal cutovers. The TMIN score showed good predictive value for both OS and PFS. In addition, The TMIN score and sex, smoke, pathological classification, American Joint Committee on Cancer stage (AJCC stage), tumor diameter and Eastern Cooperative Oncology Group-performance status (ECOG-PS) and other clinical indicators showed a strong correlation. Univariate and multivariate analyses confirmed that TMIN score was an independent risk factor for OS and PFS in NSCLC patients. It is worth noting that the TMIN nomogram model of OS and PFS based on multivariate analysis combined with TMIN score has very good prognostic value for NSCLC patients.</p><p><strong>Conclusions: </strong>TMIN is a promising predictor for PFS and OS in NSCLC patients. The TMIN-nomogram prediction model can be used as an effective tool for the comprehensive prognosis evaluation of NSCLC patients.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3392-3406"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143011990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiomicsmetabolic signature profiles for advanced non-small cell lung cancer with chemoimmunotherapy by reflecting biological function and survival.","authors":"Yuxin Jiang, Tao Liu, Ke Xu, Wanjun Lu, Qinpei Cheng, Jingyuan Xie, Mo Chen, Xiangyu Bian, Tangfeng Lv, Jiang Wu, Yong Song, Ping Zhan","doi":"10.21037/tlcr-24-576","DOIUrl":"https://doi.org/10.21037/tlcr-24-576","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Resistance to chemoimmunotherapy in patients with advanced non-small cell lung cancer (NSCLC) necessitates effective prognostic biomarkers. Although &lt;sup&gt;18&lt;/sup&gt;F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has shown potential for efficacy assessment, it has been mainly evaluated in immuno-monotherapy setting, lacking elaborations in the scenarios of immunotherapy combined with chemotherapy. To tackle this dilemma, we aimed to build a non-invasive PET/CT-based model for stratifying tumor heterogeneity and predicting survival in advanced NSCLC patients undergoing chemoimmunotherapy. Meanwhile, we explored the interplay and combined effect between programmed death-ligand 1 (PD-L1) and metabolic parameters and probed into the prognostic differences between patients with similar total metabolic tumor volume (tMTV) but different tumor distribution (lesion locations and numbers).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We retrospectively recruited unresectable advanced NSCLC patients receiving immunotherapy in Jinling Hospital from 2018 to 2023 as the training cohort. The Cancer Imaging Archive (TCIA) cohort with early-stage NSCLC patients undergoing surgical resection was used for validation and the assessment of the biological function and tumor microenvironment (TME). PET/CT-based parameters were extracted, including radiomics score (Rad-score), bone marrow to liver ratio (BLR), tMTV, and total lesion glycolysis (TLG). The end-point events included overall survival (OS) and progression-free survival (PFS). Step-wise multivariate Cox regression and the least absolute shrinkage and selection operator (LASSO) were used to identify candidate variables and establish models.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A total of 220 patients were identified for analysis, including 139 with unresectable advanced NSCLC receiving immunotherapy and 81 from TCIA. The Radiomicsmetabolicos model for OS encompassing Rad-score &gt;0.705 [hazard ratio (HR) =2.455; 95% confidence interval (CI): 1.324-4.550], squamous cell subtype (HR =1.641; 95% CI: 0.900-2.992), liver metastases (HR =3.496; 95% CI: 1.435-8.517), BLR &gt;0.94 (HR =1.885; 95% CI: 1.013-3.507), and tMTV &gt;105 mL (HR =2.162; 95% CI: 1.134-4.119) exhibited reliable prognostic capacity with a notable 3-year area under the curve (AUC) of 0.837. Patients with Rad-score ≤0.705 demonstrated upregulation of immune-related pathways and favorable survival. Additionally, distant metastases metabolic tumor volume (MTV) and TLG, as well as intrathoracic lymph nodes MTV were associated with survival independently. For patients with similar tMTV (≤105 mL), the number of FDG-avid lesions was an independent protective factor for more-than-1-year OS, which indicated that patients with smaller lesions seemed to have better long-term prognoses than those with larger lesions, even of fewer in number.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our findings proved that PET/CT could re","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3303-3322"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics of the immune microenvironment and their clinical significance in lung adenocarcinoma patients with different ALK fusion variants.","authors":"Yinbo Xiao, Hao Wang, Junliang Lu, Junyi Pang, Shiyi Liu, Yang Zhou, Xiaohua Shi, Zhiyong Liang","doi":"10.21037/tlcr-24-682","DOIUrl":"10.21037/tlcr-24-682","url":null,"abstract":"<p><strong>Background: </strong>The tumor immune microenvironment of anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinoma (LUAD) stratified by ALK fusion variants is poorly pictured. Hence, in this study, we aim to explore the immune heterogeneity of ALK⁺ LUAD across different ALK fusion variants and further investigate their significance on clinical prognosis.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on ALK⁺ LUAD patients (N=68). DNA and RNA-based next-generation sequencing (NGS) was performed to clarify the specific ALK fusion variants. Clinical and pathological characteristics were compared between long and short ALK variants. To research the immune heterogeneity, multi-fluorescence was carried out to explore the differences in immune properties, such as tumor-infiltrating lymphocyte (TIL) number, TIL subset, and tertiary lymphoid structures (TLS) development, between long and short ALK variants. Furthermore, the prognostic value of these characteristics was analyzed. Finally, the expression of lymphocyte-activation gene-3 (LAG3), one novel immune therapy target, was assessed across ALK⁺ LUAD.</p><p><strong>Results: </strong>LUAD patients with short ALK fusion variant-driven tumors exhibited higher American Joint Committee on Cancer (AJCC) stage as well as larger tumor size than those with long ALK fusion variant-driven tumors. Compared to long ALK fusion variants, there were more TILs, especially natural killer (NK) cells, within short ALK variants. However, fewer TLS were established in cancers harboring short ALK variants than those with long ALK variants. In advanced-stage LUAD patients with ALK fusion, short ALK variants, hot immune status, and high-level NK cells were identified to be adverse prognostic factors, while high-level B cells, as well as the development of TLS, served as positive prognostic factors. As for LAG3 expression, LAG3⁺ immune cells were more enriched in short ALK variants than in long ALK variants.</p><p><strong>Conclusions: </strong>LUAD patients with short ALK fusion variant-driven tumors exhibited worse prognosis than those with long ALK fusion variant-driven tumors. The tumor immune microenvironments are heterogeneous across different ALK fusion variants with short variants characterized by higher levels of TIL, especially NK cells, but by less TLS development than long variants ALK⁺ LUAD, which disfavor disease outcomes.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3538-3554"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging insights into <i>STK11</i>, <i>KEAP1</i> and <i>KRAS</i> mutations: implications for immunotherapy in patients with advanced non-small cell lung cancer.","authors":"Magdalena Knetki-Wróblewska, Kamila Wojas-Krawczyk, Paweł Krawczyk, Maciej Krzakowski","doi":"10.21037/tlcr-24-552","DOIUrl":"10.21037/tlcr-24-552","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have become an established treatment option for patients with advanced non-small cell lung cancer (NSCLC). However, the efficacy of single-agent immunotherapy as well as in combination with chemotherapy seems to be dependent on the presence of molecular abnormalities in some genes-serine/threonine kinase 11 (<i>STK11</i>), Kelch-like ECH-associated protein 1 (<i>KEAP1</i>) and Kirsten rat sarcoma viral oncogene homolog (<i>KRAS</i>) among them. The <i>KEAP1</i> gene is a critical regulator of the cellular response to oxidative stress and electrophilic stress, thus playing a pivotal role in maintaining cellular homeostasis. The <i>STK11</i> gene encodes a serine/threonine kinase (STK11) involved the regulation of cell growth, polarity, motility, differentiation and cell metabolism. The <i>STK11</i> gene mutations are often associated with an immunologically \"cold\" tumour microenvironment. The co-occurrence of <i>STK11</i> or <i>KEAP1</i> abnormalities with the <i>KRAS</i> mutation changes the composition of the tumour microenvironment as compared when presented alone. The current data, based on retrospective analyses of clinical trials, indicate that the co-existence of <i>STK11</i> and <i>KEAP1</i> genes mutations with the <i>KRAS</i> gene mutations have negative impact on the prognosis, regardless of treatment methods, in patients with advanced NSCLC. However, this group of patients should not be omitted because they constitute a significant percentage of advanced NSCLC patients. Immunotherapy focused on two ICIs [anti-programmed death 1 (PD-1)/anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)] combined with chemotherapy, may be more effective than immunotherapy or chemotherapy alone in this group of patients. Confirmation of this thesis can be found in the results of available clinical studies. Here, we summarize the theoretical justification as well as the results of clinical trials for combining immunotherapy in patients with <i>STK11</i>-, <i>KEAP1</i>- and <i>KRAS</i>-mutated genes. There is certainly a need to create a prospective clinical trial to assess the effectiveness of combined immunotherapy in the discussed group of patients.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"13 12","pages":"3718-3730"},"PeriodicalIF":4.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}