Experimental Hematology & Oncology最新文献

{"title":"Malignant pleural effusion facilitates the establishment and maintenance of tumor organoid biobank with multiple patient-derived lung tumor cell sources.","authors":"Lingwei Wang, Yanli Yu, Yanhua Fang, Yanjiao Li, Weiting Yu, Zhe Wang, Jinyan Lv, Ruoyu Wang, Shanshan Liang","doi":"10.1186/s40164-024-00581-9","DOIUrl":"10.1186/s40164-024-00581-9","url":null,"abstract":"<p><p>The Patient-Derived Organoids (PDOs) has demonstrated significant potential in personalized medicine. However, the initial establishment of lung cancer organoids (LCOs), and timely therapeutic recommendations face several challenges. Particularly, the current culture systems have not yet achieved the capability to long-term cultivation of all lung tumor sample sources, including malignant pleural effusion (MPE), which poses significant barriers to the rapid clinical translation of PDOs. Here, we established a LCOs biobank derived from various tumor cell origins and investigated the impact of supplementing culture media with MPE supernatant on organoid formation, culture duration, and drug sensitivity. Our findings indicate that MPE can enhance the successful rate of LCOs by extending the passage number and promoting the initial formation of difficult-to-culture samples, such as those derived from MPE or cell lines that were previously unsuccessful in Airway Organoid (AO) medium. MPE also facilitates the rapid proliferation of LCOs, reducing the culture duration by over 50%. Additionally, LCOs exhibit increased chemoresistance in the presence of MPE, which modifies stem cell distribution and reshapes the internal structure of the organoids. Overall, this study highlights the significance of MPE in facilitating the establishment and maintenance of LCOs, and its potential for translational applications in lung cancer research and personalized.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"115"},"PeriodicalIF":9.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural killer cell biology and therapy in multiple myeloma: challenges and opportunities.","authors":"Kamlesh Bisht, Aimee Merino, Rob Igarashi, Laurent Gauthier, Marielle Chiron, Alexandre Desjonqueres, Eric Smith, Edward Briercheck, Rizwan Romee, Evren Alici, Eric Vivier, Michael O'Dwyer, Helgi van de Velde","doi":"10.1186/s40164-024-00578-4","DOIUrl":"10.1186/s40164-024-00578-4","url":null,"abstract":"<p><p>Despite therapeutic advancements, multiple myeloma (MM) remains incurable. NK cells have emerged as a promising option for the treatment of MM. NK cells are heterogenous and typically classified based on the relative expression of their surface markers (e.g., CD56 and CD16a). These cells elicit an antitumor response in the presence of low mutational burden and without neoantigen presentation via germline-encoded activating and inhibitory receptors that identify the markers of transformation present on the MM cells. Higher NK cell activity is associated with improved survival and prognosis, whereas lower activity is associated with advanced clinical stage and disease progression in MM. Moreover, not all NK cell phenotypes contribute equally toward the anti-MM effect; higher proportions of certain NK cell phenotypes result in better outcomes. In MM, the proportion, phenotype, and function of NK cells are drastically varied between different disease stages; this is further influenced by the bone marrow microenvironment, proportion of activating and inhibitory receptors on NK cells, expression of homing receptors, and bone marrow hypoxia. Antimyeloma therapies, such as autologous stem cell transplant, immunomodulation, proteasome inhibition, and checkpoint inhibition, further modulate the NK cell landscape in the patients. Thus, NK cells can naturally work in tandem with anti-MM therapies and be strategically modulated for improved anti-MM effect. This review article describes immunotypic and phenotypic differences in NK cells along with the functional changes in homeostatic and malignant states and provides expert insights on strategies to harness the potential of NK cells for improving outcomes in MM.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"114"},"PeriodicalIF":9.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-throughput screening for optimizing adoptive T cell therapies.","authors":"Yuchen Zhang, Qinglong Xu, Zhifei Gao, Honghao Zhang, Xiaoling Xie, Meifang Li","doi":"10.1186/s40164-024-00580-w","DOIUrl":"10.1186/s40164-024-00580-w","url":null,"abstract":"<p><p>Adoptive T cell therapy is a pivotal strategy in cancer immunotherapy, demonstrating potent clinical efficacy. However, its limited durability often results in primary resistance. High-throughput screening technologies, which include both genetic and non-genetic approaches, facilitate the optimization of adoptive T cell therapies by enabling the selection of biologically significant targets or substances from extensive libraries. In this review, we examine advancements in high-throughput screening technologies and their applications in adoptive T cell therapies. We highlight the use of genetic screening for T cells, tumor cells, and other promising combination strategies, and elucidate the role of non-genetic screening in identifying small molecules and targeted delivery systems relevant to adoptive T cell therapies, providing guidance for future research and clinical applications.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"113"},"PeriodicalIF":9.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prospective pharmacotyping of urothelial carcinoma organoids for drug sensitivity prediction - feasibility and real world experience.","authors":"Michael Karl Melzer, Yanchun Ma, Jessica Lindenmayer, Clara Morgenstern, Felix Wezel, Friedemann Zengerling, Cagatay Günes, Nadine Therese Gaisa, Alexander Kleger, Christian Bolenz","doi":"10.1186/s40164-024-00579-3","DOIUrl":"10.1186/s40164-024-00579-3","url":null,"abstract":"<p><p>Urothelial carcinoma (UC) of the urinary bladder has significant challenges in treatment due to its diverse genetic landscape and variable response to systemic therapy. In recent years, patient-derived organoids (PDOs) emerged as a novel tool to model primary tumors with higher resemblance than conventional 2D cell culture approaches. However, the potential of organoids to predict therapy response in a clinical setting remains to be evaluated. This study explores the clinical feasibility of PDOs for pharmacotyping in UC. Initially, we subjected tumor tissue specimens from 50 patients undergoing transurethral resection or radical cystectomy to organoid propagation, of whom 19 (38%) yielded PDOs suitable for drug sensitivity assessment. Notably, whole transcriptome-based analysis indicated that PDOs may show phenotypes distinct from their parental tumor tissue. Pharmacotyping within a clinically relevant timeframe [mean of 35.44 and 55 days for non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC), respectively] was achieved. Drug sensitivity analyses revealed marked differences between NMIBC and MIBC, with MIBC-derived organoids demonstrating higher chemosensitivity toward clinically relevant drugs. A case study correlating organoid response with patient treatment outcome illustrated the complexity of predicting chemotherapy efficacy, especially considering the rapid acquisition of drug resistance. We propose a workflow of prospective organoid-based pharmacotyping in UC, enabling further translational research and integration of this approach into clinical practice.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"112"},"PeriodicalIF":9.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting SPP1-orchestrated neutrophil extracellular traps-dominant pre-metastatic niche reduced HCC lung metastasis.","authors":"Sun-Zhe Xie, Lu-Yu Yang, Ran Wei, Xiao-Tian Shen, Jun-Jie Pan, Shi-Zhe Yu, Chen Zhang, Hao Xu, Jian-Feng Xu, Xin Zheng, Hao Wang, Ying-Han Su, Hao-Ting Sun, Lu Lu, Ming Lu, Wen-Wei Zhu, Lun-Xiu Qin","doi":"10.1186/s40164-024-00571-x","DOIUrl":"10.1186/s40164-024-00571-x","url":null,"abstract":"<p><strong>Background: </strong>The mechanisms by which tumor-derived factors remodel the microenvironment of target organs to facilitate cancer metastasis, especially organ-specific metastasis, remains obscure. Our previous studies have demonstrated that SPP1 plays a key role in promoting metastasis of hepatocellular carcinoma (HCC). However, the functional roles and mechanisms of tumor-derived SPP1 in shaping the pre-metastatic niche (PMN) and promoting lung-specific metastasis are unclear.</p><p><strong>Methods: </strong>Orthotopic metastasis models, experimental metastasis models, CyTOF and flow cytometry were conducted to explore the function of SPP1 in shaping neutrophil-dominant PMN and promoting HCC lung metastasis. The main source of CXCL1 in lung tissues was investigated via fluorescence activated cell sorting and immunofluorescence staining. The expression of neutrophils and neutrophil extracellular traps (NETs) markers was detected in the lung metastatic lesions of HCC patients and mouse lung specimens. The therapeutic significance was explored via in vivo DNase I and CXCR2 inhibitor assays.</p><p><strong>Results: </strong>SPP1 promoted HCC lung colonization and metastasis by modifying pulmonary PMN in various murine models, and plasma SPP1 levels were closely associated with lung metastasis in HCC patients. Mechanistically, SPP1 binded to CD44 on lung alveolar epithelial cells to produce CXCL1, thereby attracting and forming neutrophil-abundant PMN in the lung. The recruited neutrophils were activated by SPP1 and then formed NETs-dominant PMN to trap the disseminated tumor cells and promote metastatic colonization. Moreover, early intervention of SPP1-orchestrated PMN by co-targeting the CXCL1-CXCR2 axis and NETs formation could efficiently inhibit the lung metastasis of HCC.</p><p><strong>Conclusions: </strong>Our study illustrates that HCC-lung host cell-neutrophil interactions play important roles in PMN formation and SPP1-induced HCC lung metastasis. Early intervention in SPP1-orchestrated PMN via CXCR2 inhibitor and DNase I is a potential therapeutic strategy to combat HCC lung metastasis.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"111"},"PeriodicalIF":9.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11556024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights into CAR T-cell hematological toxicities: manifestations, mechanisms, and effective management strategies.","authors":"Yuanyuan Yang, Hongwei Peng, Jianxiang Wang, Fei Li","doi":"10.1186/s40164-024-00573-9","DOIUrl":"10.1186/s40164-024-00573-9","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy represents a highly efficacious treatment modality demonstrated to enhance outcomes in patients afflicted with malignancies, particularly those enduring relapsed or refractory hematological malignancies. However, the escalating adoption of CAR T-cell therapy has unveiled several life-threatening toxicities, notably cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections, and hematological toxicities (HTs), thereby hindering the broad implementation of CAR T-cell therapy. HTs encompass a spectrum of adverse effects, including cytopenias, hemophagocytic lymphohistiocytosis (HLH), coagulopathies, and B-cell aplasia. While our comprehension of the underlying mechanisms governing CRS and ICANS is advancing, the intricate pathophysiology of HTs remains inadequately elucidated. Such knowledge gaps may precipitate suboptimal therapeutic decisions, potentially culminating in substantial medical resource depletion and detriment to patients' quality of life. In this comprehensive review, based on recent updated findings, we delineate various mechanisms contributing to HTs subsequent to CAR T-cell therapy, explicate manifestations of HTs, and proffer strategic interventions to mitigate this relevant clinical challenge.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"110"},"PeriodicalIF":9.4,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear porcupine mediates XRCC6/Ku70 S-palmitoylation in the DNA damage response.","authors":"Yang Chen, Mingming Xiao, Yaqi Mo, Jinlu Ma, Yamei Han, Qing Li, Qinghua Zeng, Rebecca J Boohaker, Joshua Fried, Yonghe Li, Han Wang, Bo Xu","doi":"10.1186/s40164-024-00572-w","DOIUrl":"10.1186/s40164-024-00572-w","url":null,"abstract":"<p><strong>Background: </strong>The activation of the DNA damage response (DDR) heavily relies on post-translational modifications (PTMs) of proteins, which play a crucial role in the prevention of genetic instability and tumorigenesis. Among these PTMs, palmitoylation is a highly conserved process that is dysregulated in numerous cancer types. However, its direct involvement in the DDR and the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>CRISPR-Cas9 technology was used to generate the PORCN KO and PORCN NLS KO cell lines. The effects of PORCN NLS in the DDR were verified by colony formation assays, MTT assays, the DR/EJ5 homologous recombination/non-homologous end-joining reporter system, xenograft tumor growth and immunofluorescence. Mechanisms were explored by mass spectrometry, acyl-biotin exchange (ABE) palmitoylation assay, Click-iT assay, cell subcellular fractionation assay, Western blot analysis, and in vivo and in vitro co-immunoprecipitation.</p><p><strong>Results: </strong>In this study, we introduce evidence that Porcupine (PORCN) is an integral component of and plays a critical role in the DDR. PORCN deficiency hampers nonhomologous end joining (NHEJ) and highly sensitizes cells to ionizing radiation (IR) both in vitro and in vivo. We also provide evidence that PORCN possesses a nuclear fraction (nPORCN) with S-acyltransferase activity, unlike its membrane-bound O-acyltransferase in the endoplasmic reticulum. Furthermore, we show that nPORCN is necessary for the successful activation of NHEJ. Using mass spectrometry, we reveal the existence of an nPORCN complex and show that nPORCN mediates the S-palmitoylation of XRCC6/Ku70 at five specific cysteine sites in response to IR. Mutation of these sites causes a substantial increase in radiosensitivity and delays NHEJ. Additionally, we present evidence that nPORCN-dependent Ku70 palmitoylation is required for DNA-PKcs/Ku70/Ku80 complex formation.</p><p><strong>Conclusion: </strong>Our findings underscore the crucial role of nPORCN-dependent Ku70 S-palmitoylation in the DDR.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"109"},"PeriodicalIF":9.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between O-GlcNAcylation and ubiquitination: a novel strategy for overcoming cancer therapeutic resistance.","authors":"Kai Sun, Yuan Zhi, Wenhao Ren, Shaoming Li, Jingjing Zheng, Ling Gao, Keqian Zhi","doi":"10.1186/s40164-024-00569-5","DOIUrl":"10.1186/s40164-024-00569-5","url":null,"abstract":"<p><p>Developing resistance to cancer treatments is a major challenge, often leading to disease recurrence and metastasis. Understanding the underlying mechanisms of therapeutic resistance is critical for developing effective strategies. O-GlcNAcylation, a post-translational modification that adds GlcNAc from the donor UDP-GlcNAc to serine and threonine residues of proteins, plays a crucial role in regulating protein function and cellular signaling, which are frequently dysregulated in cancer. Similarly, ubiquitination, which involves the attachment of ubiquitin to to proteins, is crucial for protein degradation, cell cycle control, and DNA repair. The interplay between O-GlcNAcylation and ubiquitination is associated with cancer progression and resistance to treatment. This review discusses recent discoveries regarding the roles of O-GlcNAcylation and ubiquitination in cancer resistance, their interactions, and potential mechanisms. It also explores how targeting these pathways may provide new opportunities to overcome cancer treatment resistance in cancer, offering fresh insights and directions for research and therapeutic development.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"107"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vertical targeting of the PI3K/AKT pathway at multiple points is synergistic and effective for non-Hodgkin lymphoma.","authors":"Kristyna Kupcova, Jana Senavova, Filip Jura, Vaclav Herman, Anezka Rajmonova, Mariana Pacheco-Blanco, Tereza Chrbolkova, Iva Hamova, R Eric Davis, Ondrej Havranek","doi":"10.1186/s40164-024-00568-6","DOIUrl":"10.1186/s40164-024-00568-6","url":null,"abstract":"<p><p>The phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway is critically active in many cell types, both normal and neoplastic. Many small-molecule inhibitors targeting different levels of the PI3K/AKT pathway have been developed for cancer therapy, but their efficacy is reduced by compensatory pathway re-activation mechanisms, and their tolerability by toxic side effects. We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT). Half-maximal (IC50) concentrations of these inhibitors for AKT activity inhibition at 1 h, when used individually, were much lower than their IC50 values for reduction of viable cell number after 4 days. Time-course studies explained this discrepancy: AKT activity in the continuous presence of the inhibitors returned to normal after 24 h, and was supranormal after inhibitor removal. Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin. Moreover, combined PDPK1 and AKT inhibition showed synergy with multiple different PI3K inhibitors. In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"108"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial immunogenomic patterns associated with lymph node metastasis in lung adenocarcinoma.","authors":"Fanjie Meng, Hao Li, Ruoyi Jin, Airong Yang, Hao Luo, Xiao Li, Peiyu Wang, Yaxing Zhao, Olga Chervova, Kaicheng Tang, Sida Cheng, Bin Hu, Yun Li, Jianpeng Sheng, Fan Yang, David Carbone, Kezhong Chen, Jun Wang","doi":"10.1186/s40164-024-00574-8","DOIUrl":"10.1186/s40164-024-00574-8","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) with lymph node (LN) metastasis is linked to poor prognosis, yet the underlying mechanisms remain largely undefined. This study aimed to elucidate the immunogenomic landscape associated with LN metastasis in LUAD.</p><p><strong>Methods: </strong>We employed broad-panel next-generation sequencing (NGS) on a cohort of 257 surgically treated LUAD patients to delineate the molecular landscape of primary tumors and identify actionable driver-gene alterations. Additionally, we used multiplex immunohistochemistry (mIHC) on a propensity score-matched cohort, which enabled us to profile the immune microenvironment of primary tumors in detail while preserving cellular metaclusters, interactions, and neighborhood functional units. By integrating data from NGS and mIHC, we successfully identified spatial immunogenomic patterns and developed a predictive model for LN metastasis, which was subsequently validated independently.</p><p><strong>Results: </strong>Our analysis revealed distinct immunogenomic alteration patterns associated with LN metastasis stages. Specifically, we observed increased mutation frequencies in genes such as PIK3CG and ATM in LN metastatic primary tumors. Moreover, LN positive primary tumors exhibited a higher presence of macrophage and regulatory T cell metaclusters, along with their enriched neighborhood units (p < 0.05), compared to LN negative tumors. Furthermore, we developed a novel predictive model for LN metastasis likelihood, designed to inform non-surgical treatment strategies, optimize personalized therapy plans, and potentially improve outcomes for patients who are ineligible for surgery.</p><p><strong>Conclusions: </strong>This study offers a comprehensive analysis of the genetic and immune profiles in LUAD primary tumors with LN metastasis, identifying key immunogenomic patterns linked to metastatic progression. The predictive model derived from these insights marks a substantial advancement in personalized treatment, underscoring its potential to improve patient management.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"106"},"PeriodicalIF":9.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}