Experimental Hematology & Oncology最新文献

{"title":"Advancing precision antibody-drug conjugate therapy: unique proteogenomic profiles of tumor subsets in non-small cell lung cancer.","authors":"Edwin Lin, Ying-Chun Lo, Vivek Subbiah, Rajat Thawani, Aakash Desai","doi":"10.1186/s40164-025-00685-w","DOIUrl":"10.1186/s40164-025-00685-w","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) represent a promising therapeutic strategy for non-small cell lung cancer (NSCLC), targeting tumor-specific antigens with precision. However, the molecular heterogeneity of NSCLC necessitates multiplex biomarker approaches to optimize ADC efficacy. This study utilized transcriptomics and proteomics to characterize NSCLC subtypes with distinct ADC target expression profiles. RNA-seq data from two independent cohorts (537 tumors, 59 controls; 338 tumors, 311 controls) identified clusters defined by overexpression of CEACAM5, MET, and TACSTD2, while normal lung tissue exhibited moderate TACSTD2 and FOLR1 expression. Chi-squared residual analysis revealed no significant associations with disease stage or driver mutations. Proteomic and transcriptomic data from 110 tumors and 101 controls demonstrated strong concordance. These findings highlight the potential of ADCs to target NSCLC subsets with distinct proteogenomic profiles, independent of disease stage or mutational status, underscoring their broad applicability in precision oncology.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"96"},"PeriodicalIF":9.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12247227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616908","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":"Reduced morbidity and mortality of cGVHD in patients who received treatment with mesenchymal stromal cells for steroid-resistant aGVHD: long-term follow-up of a randomized phase 3 trial.","authors":"Ke Zhao, Ren Lin, Zhiping Fan, Zhen Li, Xiaoyong Chen, Li Xuan, Fen Huang, Na Xu, Xiuli Wu, Shaohua Chen, Jing Sun, Xi Zhang, Jianyu Weng, Yonghua Li, Yuhua Li, Dongjun Lin, Danian Nie, Shunqing Wang, Xiaojun Xu, Xiaohui Zhang, Yangqiu Li, A P Xiang, Yu Wang, Qifa Liu","doi":"10.1186/s40164-025-00687-8","DOIUrl":"10.1186/s40164-025-00687-8","url":null,"abstract":"<p><strong>Background: </strong>Our open-label, multicenter, randomized, phase 3 trial showed that the incidence and severity of chronic graft-versus-host disease (cGVHD) reduced in steroid-resistant acute graft-versus-host disease (aGVHD) patients who underwent mesenchymal stromal cells (MSCs) treatments, but survival benefit was not received. Here, we present a post-hoc analysis of the 5-year follow-up to explore long-term survival and its underlying mechanism.</p><p><strong>Methods: </strong>This long-term follow-up trial included steroid-resistant aGVHD patients, who were randomly assigned (1:1) to receive MSCs (MSC group) (1 × 10⁶ cells/kg once weekly for 4 consecutive weeks, 8 doses at most) or without MSCs treatment (control group). For this updated analysis, the 5-year endpoints were cumulative incidence of cGVHD, overall survival, cGVHD-free, relapse-free survival (CRFS), and relapse. To explore the mechanism, We investigated the changes in T, B cells, and signal joint T cell receptor excision DNA circles (sjTRECs).</p><p><strong>Results: </strong>Between September 2014 and March 2019, 198 patients were randomly assigned to the MSC group (n = 99) or the control group (n = 99). Extended follow-up showed the lower 5-year cumulative incidence of cGVHD (42.0% [95%CI 32.2-51.5] vs. 67.1% [55.6-76.3]; hazard ratio [HR] 2.19, 95%CI 1.47-3.27; P < 0.001), improved 5-year overall survival (60.4% [50.8-70.0] vs. 41.7% [31.9-51.5]; 0.63, 0.42-0.94; P = 0.023), CRFS (33.9% [24.5-43.3] vs. 20.9% [12.9-28.9]; 0.67, 0.48-0.93; P = 0.017) and no increase on relapse (13.6% [7.6-21.3] vs. 16.0% [9.5-23.9]; 1.24, 0.60-2.56; P = 0.568) for patients in MSC group compared with the control group. Clinical improvement of MSCs was accompanied by significant increases in regulatory T cells, CD4 + CD45RA + CD31 + naïve T, CD19 + CD27 + IgD- memory B cells, and sjTRECs.</p><p><strong>Conclusions: </strong>With extended follow-up, MSCs reduced the morbidity of cGVHD in aGVHD patients and improved overall survival and CRFS. Mechanistically, MSCs reduced cGVHD by thymus pathway.</p><p><strong>Trial registration: </strong>clinicaltrials.gov identifier: NCT02241018. Registration date: 16 September 2014, https://clinicaltrials.gov/ct2/show/NCT02241018 .</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"95"},"PeriodicalIF":9.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599796","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":"Recent advances and challenges of cellular immunotherapies in lung cancer treatment.","authors":"Chengfei Yang, Yue Liu, Ziqi Huang, Sijin Liu, Xi Zhang, Quanxing Liu, Jigang Dai","doi":"10.1186/s40164-025-00679-8","DOIUrl":"10.1186/s40164-025-00679-8","url":null,"abstract":"<p><p>Lung cancer is a major malignant tumor with high morbidity and fatality rates. For many years, traditional treatments for lung cancer have struggled to achieve a favorable outlook and prognosis. It is crucial to identify and innovate novel clinical therapeutic strategies and techniques to prevent tumor progression and prolong the survival time of patients with lung cancer. Cellular immunotherapies have revolutionized the treatment of malignant tumors and have been gradually applied in clinical practice. CAR-T therapy is the best-known cellular therapy and has achieved remarkable clinical outcomes in patients with hematological malignancies, but its effect on patients with lung cancer and other solid tumors is not satisfactory, partly because of the heterogeneity and complexity of lung cancers and the sterile TMEs. To further improve the clinical effect, multiple approaches and strategies have been adopted, including discovering new tumor antigen targets, improving safety, enhancing cytotoxicity, and increasing durability. Moreover, other cell-based immunotherapies have also showed great potential for the treatment of lung cancer, including TCR-T cells, TILs, CIK cells, NK cells, macrophages, and dendritic cells, which enriched the number of treatment choices for patients with lung cancer. In summary, the present article summarizes and highlights recent advances and challenges in the use of cellular immunotherapies for the treatment of lung cancer, which might stimulate new ideas for the further development of cellular immunotherapies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"94"},"PeriodicalIF":9.4,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583494","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":"iPSC-derived NK cells engineered with CD226 effectively control acute myeloid leukemia.","authors":"Runze Cai, Binyan Lu, Xiangyu Zhao, Shixin Zhou, Yang Li","doi":"10.1186/s40164-025-00686-9","DOIUrl":"10.1186/s40164-025-00686-9","url":null,"abstract":"<p><p>CD226 plays a vital role in NK cell cytotoxicity, interacting with its ligands on tumor targets. Acute myeloid leukemia (AML) cells have developed mechanisms to escape NK cell cytotoxicity, including inducing downregulation of CD226 on NK cells. Induced pluripotent stem cell -derived NK (iPSC-NK) cells offer an important source of standardized off-the-shelf NK cell therapy to treat AML patients. In this study, we engineered iPSC-NK cells with CD226 to assess the ability of killing AML cells. iPSC-NK cells engineered with CD226 have a typical NK cell phenotype and demonstrate improved anti-AML activity and multiple cytokines releasing at low effector-to-target ratios. Transcriptomic analysis revealed upregulation of immune effector function pathways associated with cytotoxicity and immune activation in CD226-overexpression iPSC-NK cells. In an AML xenograft model, mice treated with CD226 overexpression iPSC-NK cells exhibited significantly reduced leukemia burden, prolonged survival, decreased systemic inflammation compared to those treated with Control iPSC-NK cells. Overall, our study provided evidence that iPSC derived-NK cells engineered with CD226 represent a promising candidate for off-the-shelf immunotherapy, particularly in AML and other CD226 ligand-expressing malignancies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"93"},"PeriodicalIF":9.4,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583493","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":"Current challenges and emerging opportunities of chimeric antigen receptor-engineered cell immunotherapy.","authors":"Yong Liu, Yifei Duan, Zefan Du, Bo Lu, Su Liu, Lindi Li, Mengyao Tian, Liang Li, Ran Yao, Cheng Ouyang, Mo Yang, Chun Chen","doi":"10.1186/s40164-025-00683-y","DOIUrl":"10.1186/s40164-025-00683-y","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) engineered cellular immunotherapy offers the potential for precise targeting and elimination of tumor cells, providing a tailored approach to cancer treatment. CAR-T cells demonstrate significant anti-tumor activity among these therapies. Nonetheless, these therapies may trigger adverse effects, including inflammatory and neurotoxic reactions during treatment. Recent efforts have been directed toward enhancing efficacy by optimizing CAR design or modulating its activity. Compared to CAR-T cells, CAR-engineered natural killer cells (CAR-NK) present notable advantages, including various sources and diminished toxicity, and are gaining recognition in clinical research. CAR-macrophages (CAR-M), while sharing antigenic domains similar to those of CAR-T cells, display superior capabilities in antigen presentation and tumor penetration. As a result, there is significant enthusiasm surrounding investigations into CAR-NK and CAR-M cell immunotherapies. This review explores the existing environment and obstacles associated with immunotherapies that utilize CAR-T, CAR-NK, and CAR-M cells to inspire novel pathways for forthcoming clinical applications.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"92"},"PeriodicalIF":9.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552740","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":"Prophylactic infusion of allogeneic double-negative T cells as immune modulators to prevent relapse in high-risk AML patients post-Allo-HSCT: a phase I trial.","authors":"Guangyu Sun, Xingchi Chen, Tianzhong Pan, Kaidi Song, Haicun Xie, Meijuan Tu, Xiang Wan, Wen Yao, Yaxin Cheng, Ziwei Zhou, Dongyao Wang, Yongsheng Han, Baolin Tang, Liming Yang, Xiaoyu Zhu","doi":"10.1186/s40164-025-00680-1","DOIUrl":"10.1186/s40164-025-00680-1","url":null,"abstract":"<p><p>Relapse remains a major challenge for high-risk acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT). In our first-in-human Phase I trial (ChiCTR-1900022795), we have demonstrated that third-party donor-derived double-negative T cells (DNTs) are safe and effective for treating relapsed AML. This Phase I study aims to further evaluate the safety and efficacy of allo-DNTs in preventing relapse in AML patients post-allo-HSCT. Six high-risk AML patients received three infusions of off-the-shelf allo-DNTs at one-month intervals, administered 60 to 100 days post-allo-HSCT without lymphodepleting chemotherapy. No dose-limiting toxicity, DNT-related graft-versus-host disease (GvHD), or severe cytokine release syndrome (CRS) occurred. With a median follow-up of 20.9 months (range: 11.4-24.6), four patients (66.7%) remained in minimal residual disease (MRD)-negative complete remission (CR), with recurrence-free survival exceeding 24 months. Patients in remission showed increased CD8⁺ and CD4⁺ T cells, total DNTs, and higher frequencies of granzyme-secreting T cells, which were absent in relapsed patients. In vitro, co-culturing AML patient CD8⁺ T cells with allo-DNTs upregulated granzyme B and interferon-γ expression, indicating CD8⁺ T cell activation. These findings suggest that allogeneic DNT immunotherapy is a safe, promising strategy to prevent relapse in high-risk AML patients post-allo-HSCT by combining intrinsic antitumor activity with immune modulation.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"90"},"PeriodicalIF":9.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552741","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":"Bladder cancer subtypes exhibit limited plasticity across different microenvironments and in metastases.","authors":"Carina Bernardo, Subhayan Chattopadhyay, Natalie Andersson, Pontus Eriksson, Benjamin Medle, Lena Tran, Nour Al Dain Marzouka, Adam Mattsson, Aymeric Zadoroznyj, Malin Larsson, Fredrik Liedberg, Mattias Höglund, Gottfrid Sjödahl","doi":"10.1186/s40164-025-00682-z","DOIUrl":"10.1186/s40164-025-00682-z","url":null,"abstract":"<p><strong>Background: </strong>Transcriptomic and genomic analyses of bladder cancer (BC) reveal a highly diverse disease stratified into molecular subtypes with distinct molecular features and biological behaviors. Intratumor heterogeneity (ITH) and plasticity can significantly impact diagnosis and patient management, yet their extent in BC remains highly debated. Here, we investigated whether the three main bladder cancer subtypes maintain or alter their identity in response to changes in the microenvironment and during metastatic colonization.</p><p><strong>Methods: </strong>Seven patient-derived xenograft (PDX) models representing the major BC subtypes were propagated into three distinct tissue microenvironments: subcutaneous, mammary fat pad and under the kidney capsule. Metastatic lesions were generated via systemic injection of tumor cells. Tumor samples were analysed using RNA- and exome sequencing, SNP-arrays and histopathology to assess subtype fidelity, genomic evolution, and clonal dynamics.</p><p><strong>Results: </strong>A comprehensive, longitudinal multiomics analysis showed that tumors consistently maintain their molecular subtype, as well as their transcriptomic and genomic profiles, across different environments. No evidence of emerging ITH or subtype transitions was observed, regardless of the microenvironment. The transcriptomic adaptations observed in metastases and different implantation sites are limited and are associated primarily with hypoxia, epithelial-mesenchymal transition (EMT), and invasion.</p><p><strong>Conclusions: </strong>Our results suggest that invasive bladder cancers have a strong intrinsic tumor identity that is not easily reprogrammed by the microenvironment.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"91"},"PeriodicalIF":9.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12225047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552739","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":"Mitotic MTH1 inhibitor karonudib kills epithelial ovarian cancer independent of platinum sensitivity.","authors":"Rachel M Hurley, Jill M Wagner, Arun Kanakkanthara, Annapoorna Venkatachalam, Aaron M Deisinger, Cristina Correia, Paula A Schneider, Kevin L Peterson, Elaine P Macon, Ethan P Heinzen, Kumar Sanjiv, Xiaonan Hou, Marc A Becker, Matthew J Maurer, Melissa C Larson, Elizabeth M Swisher, Hu Li, Ann L Oberg, S John Weroha, Ulrika Warpman Berglund, Thomas Helleday, Scott H Kaufmann, Andrea E Wahner Hendrickson","doi":"10.1186/s40164-025-00681-0","DOIUrl":"10.1186/s40164-025-00681-0","url":null,"abstract":"<p><p>The prognosis for women with ovarian cancer (OC) is particularly poor if resistance to platinum compounds, the mainstay of standard-of-care therapy, develops. Inhibitors of the Nudix hydrolase MuT Homolog 1 (MTH1) have previously been shown to arrest cancer cells in mitosis, increase 8-oxo-2'-deoxyguanosine (8-oxo-dG) incorporation into DNA, and selectively kill neoplastic cells while sparing normal cells. Here we explored the cytotoxic mechanism of these agents as well as their activity against platinum-resistant OC in vitro and in vivo. Two mitotic MTH1 inhibitors (mMTH1is), TH588 and karonudib, decreased colony formation indistinguishably in platinum-sensitive OC cell lines and their platinum-resistant counterparts in vitro but had limited effects on fallopian tube and immortalized ovarian surface epithelial cells. Treatment with karonudib stalled OC cells in mitosis and caused elevated 8-oxo-dG levels in DNA followed by activation of base excision repair, induction of BAX, and apoptotic cellular demise. This cytotoxicity was blunted by overexpression of the pre-mitotic checkpoint protein CHFR, which inhibits other anti-mitotics, or treatment with the antioxidant N-acetylcysteine, which diminishes nuclear 8-oxo-dG staining, suggesting a role for both mitotic stalling and increased nuclear incorporation of oxidized nucleotides in karonudib efficacy. In three orthotopic OC patient-derived xenograft models, karonudib monotherapy induced growth delay in vivo. Moreover, addition of karonudib to carboplatin doubled median overall survival in two models and prolonged survival for the duration of the study (110 days) in the third. These results demonstrate activity of mMTH1is as monotherapy and in combination with carboplatin in OC that warrants further investigation.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"88"},"PeriodicalIF":13.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474393","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 cereblon expression in neuroendocrine cancer confers vulnerability to GSPT1 molecular glue degrader.","authors":"Jaewoo Park, Min Sung Joo, Myung Jun Kim, Seungseok Oh, Phuong Thao Tran, Minju Kwon, Yong June Choi, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Wooseok Han, Keon Wook Kang","doi":"10.1186/s40164-025-00674-z","DOIUrl":"10.1186/s40164-025-00674-z","url":null,"abstract":"<p><strong>Background: </strong>Recent advances in targeted therapies have introduced molecular glue degraders (MGDs) that leverage the cereblon (CRBN) E3 ubiquitin ligase to degrade the translation termination factor GSPT1. Understanding the cellular context for the selective targeting of cancer cells by GSPT1 MGDs is crucial.</p><p><strong>Methods: </strong>This study investigated the sensitivity of neuroendocrine cancer (NEC) cells to GSPT1MGDs across a pan-cancer cell line panel, examining the correlation between therapeutic response and cellular characteristics such as CRBN expression and neuroendocrine (NE) marker levels. The role of CRBN in enhancing MGD sensitivity was further validated through CRBN overexpression and NEC-driving factor expression experiments in non-NEC and lung adenocarcinoma cells. The sensitivity of acute myeloid leukemia (AML) cells, which share transcriptomic features with NECs, to GSPT1 MGDs was also evaluated.</p><p><strong>Results: </strong>NEC cells with high CRBN expression exhibited marked sensitivity to GSPT1 MGDs compared to other cancer types. GSPT1 degradation was more rapid and robust in NEC cells, highlighting the cellular context dependency of the treatment. A strong correlation was observed between CRBN expression and NE characteristics, whereas no such correlation was found with GSPT1 expression. CRBN overexpression in non-NEC cells significantly increased their sensitivity to GSPT1 MGDs, as did the ectopic expression of NEC-driving factors, which upregulated CRBN levels in lung adenocarcinoma cells. Additionally, AML cells, with high CRBN expression, showed similar sensitivity to GSPT1 MGDs, mirroring the behavior of NECs.</p><p><strong>Conclusions: </strong>CRBN expression is a critical determinant of the selective cytotoxicity of GSPT1 MGDs in NECs and other cancers with shared transcriptomic features, such as AML. These findings underscore the therapeutic potential of targeting NECs using GSPT1 MGDs, paving the way for a more refined and selective approach in treating aggressive cancers.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"89"},"PeriodicalIF":9.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474392","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":"Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer.","authors":"Mengyue Lei, Jessica Gai, Thomas J McPhaul, Huijuan Luo, Penghui Lin, Dongbing Liu, Michael Pishvaian, Nicholas J Roberts, Kui Wu, Jin He, Lei Zheng","doi":"10.1186/s40164-025-00673-0","DOIUrl":"10.1186/s40164-025-00673-0","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. However, PDAC with germline BRCA mutations, which lead to homologous recombination (HR) deficiency (HRD), demonstrated an increased sensitivity to platinum-based chemotherapy regimens. This increased chemosensitivity was also seen in PDACs with germline or somatic mutations in the DNA double-strand damage response (DDR) genes beyond canonical HR genes such as BRCA1, BRCA2, and PALB2. However, there are no consensus methods to determine HRD status; and neither is there a well-defined list of HR-DDR genes. In addition, how HRD and/or HR-DDR gene mutation status impacts the tumor immune microenvironment including tumor mutation burden (TMB), neoantigen load, T cell receptor (TCR) repertoire, and effector T cell infiltration is unknown. Thus, in this study, we developed a new method to categorize PDACs into HRD-positive and HRD-negative subgroups by using results from whole exome sequencing, whole genome sequencing, or both into consideration. We classified a cohort of 89 PDACs into HRD-positive (n = 18) and HRD-negative (n = 69) tumors. HR-DDR gene variants were identified more frequently in HRD-positive PDACs than HRD-negative PDACs, with RAD51B, BRCA2 and ATM alterations most frequently identified in HRD-positive PDACs. Notably, TMB and neoantigen load was significantly higher in HRD-positive PDACs compared to HRD-negative tumors. Interestingly, HRD-positive PDACs, PDACs with high tumor mutational burden, and PDAC with high neoantigen load were all associated with lower CD8 + T lymphocyte infiltration and T cell clonal diversity, suggesting a mechanism of resistance to immune checkpoint inhibitors (ICIs). Therefore, this study suggests that treatments to enhance effector T cell infiltration and T cell clonal diversity may overcome resistance to ICI-based immunotherapy in HRD-positive PDACs.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"86"},"PeriodicalIF":9.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324897","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}