bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2025–04–06
twelve papers selected by
Sergio Marchini, Humanitas Research
  1. Copy number variations in endometrial cancer: from biological significance to clinical utility.
  2. CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.
  3. Genome-wide cell-free DNA methylation profiling in advanced stage ovarian cancer. Are we looking at the tumor or the patient's immune response to the tumor?
  4. Cell-free DNA Fragmentomics Assay to Discriminate the Malignancy of Breast Nodules and Evaluate Treatment Response.
  5. Computational analysis of DNA methylation from long-read sequencing.
  6. Mutational profiling using liquid biopsy to guide targeted therapy in patients with metastatic cancer.
  7. Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers.
  8. The DNA methylation landscape of primary triple-negative breast cancer.
  9. The challenge of managing isolated STIC lesions: A single-center experience.
  10. Patient-reported outcomes from the MIRASOL trial evaluating mirvetuximab soravtansine versus chemotherapy in patients with folate receptor α-positive, platinum-resistant ovarian cancer: a randomised, open-label, phase 3 trial.
  11. SpaGRN: Investigating spatially informed regulatory paths for spatially resolved transcriptomics data.
  12. An automatic annotation tool and reference database for T cell subtypes and states at single-cell resolution.
  1. Int J Gynecol Cancer. 2024 Jul;pii: S1048-891X(24)01441-5. [Epub ahead of print]34(7): 1089-1097
    Copy number variations in endometrial cancer: from biological significance to clinical utility.
    Erica Dugo, Francesco Piva, Matteo Giulietti, Luca Giannella, Andrea Ciavattini, Linda Gough.
      The molecular basis of endometrial cancer, which is the most common malignancy of the female reproductive organs, relies not only on onset of mutations but also on copy number variations, the latter consisting of gene gains or losses. In this review, we introduce copy number variations and discuss their involvement in endometrial cancer to determine the perspectives of clinical applicability. We performed a literature analysis on PubMed of publications over the past 30 years and annotated clinical information, including histological and molecular subtypes, adopted molecular techniques for identification of copy number variations, their locations, and the genes involved. We highlight correlations between the presence of some specific copy number variations and myometrial invasion, lymph node metastasis, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, high grade, drug response, and cancer progression. In particular, type I endometrial cancer cells have few copy number variations and are mainly located in 8q and 1q, while type II, high grade, and advanced FIGO stage endometrial cancer cells are aneuploid and have a greater number of copy number variations. As expected, the higher the number of copy number variations the worse the prognosis, especially if they amplify CCNE1, ERBB2, KRAS, MYC, and PIK3CA oncogenes. Great variability in copy number and location among patients with the same endometrial cancer histological or molecular subtype emerged, making them interesting candidates to be explored for the improvement of patient stratification. Copy number variations have a role in endometrial cancer progression, and therefore their detection may be useful for more accurate prediction of prognosis. Unfortunately, only a few studies have been carried out on the role of copy number variations according to the molecular classification of endometrial cancer, and even fewer have explored the correlation with drugs. For these reasons, further studies, also using single cell RNA sequencing, are needed before reaching a clinical application.
    Keywords:  Carcinoma; Endometrial Neoplasms; Homologous recombination
    DOI:  https://doi.org/10.1136/ijgc-2024-005295
  2. PLoS Comput Biol. 2025 Apr 03. 21(4): e1012902
    CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.
    Khanh N Dinh, Ignacio Vázquez-García, Andrew Chan, Rhea Malhotra, Adam Weiner, Andrew W McPherson, Simon Tavaré.
      Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, [Formula: see text] ). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas ([Formula: see text]) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, [Formula: see text]). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012902
  3. Cancer Treat Res Commun. 2025 Mar 22. pii: S2468-2942(25)00041-3. [Epub ahead of print]43 100903
    Genome-wide cell-free DNA methylation profiling in advanced stage ovarian cancer. Are we looking at the tumor or the patient's immune response to the tumor?
    Caroline B van den Berg, Gatske M Nieuwenhuyzen-de Boer, Ingrid A Boere, Ruben G Boers, Joachim B Boers, Wilfred F J van-IJcken, Maurice P H M Jansen, Tugce S Kirmizitas, Joost H Gribnau, Heleen J van Beekhuizen.
      The aim of this study was to identify differentially methylated regions in cell-free DNA (cfDNA) between healthy persons and patients with advanced stage ovarian cancer (ASOC) and to identify differences in cfDNA methylation before and after cytoreductive surgery. Plasma-derived cfDNA was analyzed by a high-throughput genome wide DNA methylation sequencing technique: MeD-seq. A training set of therapy naïve cfDNA samples of patients with ASOC (≥FIGO stage IIIB, n=10) was compared with cfDNA of healthy controls (n=10) to define a ASOC specific cfDNA methylation signature. A cumulative hypermethylation score was constructed and a validation set of pre- and postoperative samples of 39 patients were compared using this score. MeD-seq results of tumor tissue samples were correlated with cfDNA results. Patients with ASOC showed a clear distinct cfDNA methylation signature from healthy controls (p<0.0001). This cfDNA-methylation signature resulted in preoperative hypermethylation scores (135; interquartile range 110-163) that were significantly higher than postoperative hypermethylation scores (91; interquartile range 76-101) (p<0.001). The cfDNA methylation signature at baseline differed from tumor tissue and was more closely related to DNA methylation of immune-related cells (T-lymphocytes, neutrophil granulocytes, monocytes, and B-lymphocytes) than to ASOC tissue. MeD-seq provides a promising method for genome wide methylation profiling of cfDNA. Patients with ASOC could clearly be distinguished from healthy controls and differed pre- and postoperatively.
    Keywords:  DNA methylation; Liquid biopsy; MeD-seq; Ovarian cancer; cell free DNA
    DOI:  https://doi.org/10.1016/j.ctarc.2025.100903
  4. Genomics Proteomics Bioinformatics. 2025 Apr 04. pii: qzaf028. [Epub ahead of print]
    Cell-free DNA Fragmentomics Assay to Discriminate the Malignancy of Breast Nodules and Evaluate Treatment Response.
    Jiaqi Liu, Yalun Li, Wanxiangfu Tang, Tianyi Qian, Lijun Dai, Ziqi Jia, Heng Cao, Chenghao Li, Yuchen Liu, Yansong Huang, Jiang Wu, Dongxu Ma, Guangdong Qiao, Hua Bao, Shuang Chang, Dongqin Zhu, Shanshan Yang, Xuxiaochen Wu, Xue Wu, Hengyi Xu, Hongyan Chen, Yang Shao, Xiang Wang, Zhihua Liu, Jianzhong Su.
      The fragmentomics-based cell-free DNA (cfDNA) assays have recently illustrated prominent abilities to identify various cancers from non-conditional healthy controls, while their accuracy for identifying early-stage cancers from benign lesions with inconclusive imaging results remains uncertain. Especially for breast cancer, current imaging-based screening methods suffer from high false positive rates for women with breast nodules, leading to unnecessary biopsies, which add to discomfort and healthcare burden. Here, we enrolled 613 female participants in this multi-center study and demonstrated that cfDNA fragmentomics (cfFrag) is a robust non-invasive biomarker for breast cancer using whole-genome sequencing. Among the multimodal cfFrag profiles, the fragment size ratio (FSR), fragment size distribution (FSD), and copy number variation (CNV) show more distinguishing ability than Griffin, motif breakpoint (MBP), and neomer. The cfFrag model using the optimal three fragmentomics features discriminated early-stage breast cancers from benign nodules, even at a low sequencing depth (3×). Notably, it demonstrated a specificity of 94.1% in asymptomatic healthy women at a 90% sensitivity for breast cancers. Moreover, we comprehensively showcased the clinical utilities of the cfFrag model in predicting patient responses to neoadjuvant chemotherapy (NAC) and in combining with multimodal features, including radiological results and cfDNA methylation features [with area under the curve (AUC) values of 0.93-0.94 and 0.96, respectively].
    Keywords:  Breast cancer; Cell-free DNA methylation; Fragmentomics; Neoadjuvant chemotherapy; Whole-genome sequencing
    DOI:  https://doi.org/10.1093/gpbjnl/qzaf028
  5. Nat Rev Genet. 2025 Mar 28.
    Computational analysis of DNA methylation from long-read sequencing.
    Yilei Fu, Winston Timp, Fritz J Sedlazeck.
      DNA methylation is a critical epigenetic mechanism in numerous biological processes, including gene regulation, development, ageing and the onset of various diseases such as cancer. Studies of methylation are increasingly using single-molecule long-read sequencing technologies to simultaneously measure epigenetic states such as DNA methylation with genomic variation. These long-read data sets have spurred the continuous development of advanced computational methods to gain insights into the roles of methylation in regulating chromatin structure and gene regulation. In this Review, we discuss the computational methods for calling methylation signals, contrasting methylation between samples, analysing cell-type diversity and gaining additional genomic insights, and then further discuss the challenges and future perspectives of tool development for DNA methylation research.
    DOI:  https://doi.org/10.1038/s41576-025-00822-5
  6. Sci Rep. 2025 Apr 01. 15(1): 11135
    Mutational profiling using liquid biopsy to guide targeted therapy in patients with metastatic cancer.
    Omayma Mazouji, Abdelhak Ouhajjou, Naima Anouar, Chakib Nejjari, Roberto Incitti, Hicham Mansour.
      Liquid biopsy gained significant interest in the area of cancer management. This study aims to evaluate the effectiveness of molecular testing using ctDNA (circulating tumor DNA) to; detect genetic alterations, screen for abnormalities, identify mutations associated with treatment sensitivity or resistance and guide therapy decision for several types of cancer in patients with metastasis. A total of 85 samples were collected from 74 patients recruited at our center, as part of their routine clinical follow-up. 17 different cancer types were analyzed. Genetic testing was conducted in patients with metastasis after failure of standard treatments. Sequencing was conducted in plasma-ctDNA samples; and when it was possible on the tumor tissue as well. Our analysis revealed that 88% (65 patients) of patients were eligible for treatment guidance using liquid biopsy. Among them, 64% (47 patients) received an FDA-approved drug, and treatment decisions were based on molecular testing using ctDNA. Somatic gene mutations were detected in 89% (66 patients) of the patients tested; 81% (60 patients) of patients had at least two mutations, 8% (6 patients) had only one mutation and 11% (8 patients) had no detected mutations. Interestingly, among the genes tested, BRCA2, EGFR, MSH6, and NF1 were the most frequently mutated in our patients. Our study highlights the potential benefits of personalized medicine through a non-invasive genetic testing across patients with metastasis regardless of the cancer types. Moreover, our study identified the frequent occurrence of specific gene mutations across various types of cancer, which paves the way for considering targeted therapies that could be applicable to multiple cancer types, rather than being restricted to just a few.
    Keywords:  Cancers; Liquid biopsy; Metastasis; Treatment guidance
    DOI:  https://doi.org/10.1038/s41598-025-88094-1
  7. Nat Rev Clin Oncol. 2025 Apr 03.
    Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers.
    Margherita Ambrosini, Paolo Manca, Vincenzo Nasca, Carolina Sciortino, Filippo Ghelardi, Jenny F Seligmann, Julien Taieb, Filippo Pietrantonio.
      Deficiency in DNA mismatch repair (dMMR) is a common pathway of carcinogenesis across different tumour types and confers a characteristic microsatellite instability-high (MSI-H) molecular phenotype. The prevalence of the MSI-H/dMMR phenotype is highest in endometrial and colorectal cancers, and this phenotype is associated with a distinct tumour biology, prognosis and responsiveness to various anticancer treatments. In a minority of patients, MSI-H/dMMR cancers result from an inherited pathogenic variant in the context of Lynch syndrome, which has important implications for familial genetic screening. Whether these hereditary cancers have a different biology and clinical behaviour to their sporadic counterparts remains uncertain. Interest in this tumour molecular subtype has increased following the discovery of the high sensitivity of metastatic MSI-H/dMMR cancers to immune-checkpoint inhibitors (ICIs) in a histology-agnostic manner, which reflects the genomic hypermutation resulting from dMMR that renders these tumours highly immunogenic and immune infiltrated. This vulnerability is now also being exploited in early stage disease settings. Despite this common biological foundation, different MSI-H/dMMR cancers have histotype-specific features that correspond to their particular cell or tissue of origin, which might be associated with differences in prognosis and sensitivity to ICIs. In this Review, we provide an overview of the epidemiology, biology, pathogenesis, clinical diagnosis and treatment of MSI-H/dMMR tumours as a histology-agnostic cancer phenomenon. We also highlight peculiarities associated with specific pathogenetic alterations and histologies of MSI-H/dMMR tumours.
    DOI:  https://doi.org/10.1038/s41571-025-01015-z
  8. Nat Commun. 2025 Mar 28. 16(1): 3041
    The DNA methylation landscape of primary triple-negative breast cancer.
    Mattias Aine, Deborah F Nacer, Elsa Arbajian, Srinivas Veerla, Anna Karlsson, Jari Häkkinen, Henrik J Johansson, Frida Rosengren, Johan Vallon-Christersson, Åke Borg, Johan Staaf.
      Triple-negative breast cancer (TNBC) is a clinically challenging and molecularly heterogenous breast cancer subgroup. Here, we investigate the DNA methylation landscape of TNBC. By analyzing tumor methylome profiles and accounting for the genomic context of CpG methylation, we divide TNBC into two epigenetic subtypes corresponding to a Basal and a non-Basal group, in which characteristic transcriptional patterns are correlated with DNA methylation of distal regulatory elements and epigenetic regulation of key steroid response genes and developmental transcription factors. Further subdivision of the Basal and non-Basal subtypes identifies subgroups transcending genetic and proposed TNBC mRNA subtypes, demonstrating widely differing immunological microenvironments, putative epigenetically-mediated immune evasion strategies, and a specific metabolic gene network in older patients that may be epigenetically regulated. Our study attempts to target the epigenetic backbone of TNBC, an approach that may inform future studies regarding tumor origins and the role of the microenvironment in shaping the cancer epigenome.
    DOI:  https://doi.org/10.1038/s41467-025-58158-x
  9. Gynecol Oncol Rep. 2025 Apr;58 101716
    The challenge of managing isolated STIC lesions: A single-center experience.
    Renata Sabelli, Basile Tessier-Cloutier, Lili Fu, Shuk On Annie Leung, Xing Zeng, Reitan Ribeiro, Victoria Mandilaras, Lucy Gilbert, Laurence Bernard.
       Objectives: High-grade serous carcinoma (HGSC) arise from serous tubal intraepithelial carcinoma (STIC) lesions, a precursor that develops from the fallopian tube epithelium. Patients with incidental isolated STIC lesions found on salpingectomy specimen have up to 25% risk of developing HGSC or peritoneal carcinomatosis in the future, yet there is no established consensus to guide management.
    Methods: This retrospective case series includes patients diagnosed with isolated STIC lesions between April 2017 and January 2024. Patient data was extracted from clinical and pathological databases.
    Results: During the study period, 10 patients were diagnosed with an isolated STIC lesion. The fallopian tubes were removed either as part of a hysterectomy for endometrial cancer (n = 3); a prophylactic risk-reducing surgery for BRCA1 or BRCA2 mutation (n = 3); or a benign gynecologic condition (n = 4). The median age of the patients was 64 years (range: 53-80). Among patients who underwent genetic testing (n = 9), only three were found to have a deleterious germline mutation in BRCA1 or BRCA2. The patients either received adjuvant chemotherapy (n = 5) or underwent active surveillance (n = 5). One surveillance patient was managed with completion bilateral oophorectomy and omentectomy. Median number of chemotherapy cycles was four (range 4-6 cycles). The median follow-up was 27 months (range: 5-83 months). One patient under active surveillance was diagnosed with peritoneal carcinomatosis 5 years after initial diagnosis of STIC whereas none recurred in the chemotherapy group.
    Conclusion: The wide variety of treatment approaches we observed highlights a need for more data on this entity to support management guidelines.
    Keywords:  Adjuvant Chemotherapy; High-grade serous ovarian cancer (HGSC); Management & Treatment.; Peritoneal carcinomatosis (PC); Serous Tubal Intraepithelial Carcinoma (STIC)
    DOI:  https://doi.org/10.1016/j.gore.2025.101716
  10. Lancet Oncol. 2025 Apr;pii: S1470-2045(25)00021-X. [Epub ahead of print]26(4): 503-515
    Patient-reported outcomes from the MIRASOL trial evaluating mirvetuximab soravtansine versus chemotherapy in patients with folate receptor α-positive, platinum-resistant ovarian cancer: a randomised, open-label, phase 3 trial.
    Toon Van Gorp, Kathleen N Moore, Gottfried E Konecny, Alexandra Leary, Yolanda García-García, Susana Banerjee, Domenica Lorusso, Jung-Yun Lee, John W Moroney, Giuseppe Caruso, Dagmara Klasa-Mazurkiewicz, Jacqueline Tromp, Lainie P Martin, Shani Breuer, Charles A Leath, David Cibula, S John Weroha, Purificación Estévez-García, David M O'Malley, Rowan E Miller, Lan Coffman, Giuseppa Scandurra, Dominique Berton, Lingling Li, Erin Zagadailov, Elisabeth J Diver, Olivier Trédan, Felix Hilpert.
       BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV) is a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), approved by the US Food and Drug Administration for the treatment of platinum-resistant ovarian cancer in the USA. Here, we report patient-reported outcomes for participants treated with MIRV compared with investigator's choice of chemotherapy from the phase 3 MIRASOL trial, which met its primary endpoint of progression-free survival and key secondary endpoints of objective response rate and overall survival.
    METHODS: The MIRASOL trial was a confirmatory, phase 3, randomised, controlled, open-label trial, building on the phase 2 SORAYA trial which had previously demonstrated the safety and efficacy of MIRV in platinum-resistant ovarian cancer. Patients 18 years or older with a confirmed platinum-resistant, recurrent high-grade serous epithelial ovarian cancer diagnosis were recruited from 253 sites including hospitals, academic centres, and community centres in 21 countries. Patients must have received one to three previous systemic anticancer therapies, and have high FRα tumour expression (≥75% tumour cells with an immunohistochemistry score of ≥2+ membrane staining using the PS2+ scoring method), one or more lesions with measurable disease, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to MIRV or investigator's choice of chemotherapy, stratified by number of previous therapy lines and the type of investigator's choice of chemotherapy. Therapies were administered in an open-label manner; MIRV was administered intravenously at 6 mg/kg of adjusted ideal bodyweight every 3 weeks. The primary endpoint was progression-free survival. Key secondary endpoints were objective response rate, overall survival, and a 15·0-point or greater improvement at week 8 or 9 in abdominal and gastrointestinal symptoms using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Ovarian Cancer Module (EORTC QLQ-OV28) in the intention-to-treat population. The MIRASOL trial was registered at ClinicalTrials.gov (NCT04209855), the Gynecologic Oncology Group (GOG 3045), and the European Network of Gynaecological Oncological Trial Groups (ENGOT-ov55), and is complete.
    FINDINGS: Between Feb 3, 2020, and Aug 3, 2022, 453 patients were enrolled and randomly assigned to treatment (227 to the MIRV group and 226 to the investigator's choice of chemotherapy group). All patients were female; 301 (66%) participants were White, 53 (12%) were Asian, 13 (3%) were Black, and 86 (19%) were of another race or not reported; 27 (6%) were Hispanic or Latino. The median follow-up for the study, determined by the reverse Kaplan-Meier method, was 13·1 months (95% CI 12·1-14). QLQ-OV28 completion rates were 86% (365 of 425) at baseline and 81% (282 of 349) at week 8 or 9. 34 (21·0%; 95% CI 15·0-28·1) of 162 patients treated with MIRV reported improvement in QLQ-OV28 abdominal and gastrointestinal scores, compared with 23 (15·3%; 10·0-22·1) of 150 patients treated with the investigator's choice of chemotherapy. These differences were not statistically significant (odds ratio 1·5 [95% CI 0·8-2·6]; p=0·26).
    INTERPRETATION: MIRV did not seem to impair or improve patient quality of life compared with investigator's choice of chemotherapy. The similar quality-of-life outcomes in the two treatment groups, combined with the previously reported higher efficacy of MIRV compared with single-agent chemotherapy, support MIRV as new treatment option for FRα-positive platinum-resistant ovarian cancer.
    FUNDING: AbbVie.
    DOI:  https://doi.org/10.1016/S1470-2045(25)00021-X
  11. Cell Syst. 2025 Mar 27. pii: S2405-4712(25)00076-6. [Epub ahead of print] 101243
    SpaGRN: Investigating spatially informed regulatory paths for spatially resolved transcriptomics data.
    Yao Li, Xiaobin Liu, Lidong Guo, Kai Han, Shuangsang Fang, Xinjiang Wan, Dantong Wang, Xun Xu, Ling Jiang, Guangyi Fan, Mengyang Xu.
      Cells spatially organize into distinct cell types or functional domains through localized gene regulatory networks. However, current spatially resolved transcriptomics analyses fail to integrate spatial constraints and proximal cell influences, limiting the mechanistic understanding of tissue organization. Here, we introduce SpaGRN, a statistical framework that reconstructs cell-type- or functional-domain-specific, dynamic, and spatial regulons by coupling intracellular spatial regulatory causality with extracellular signaling path information. Benchmarking across synthetic and real datasets demonstrates SpaGRN's superior precision over state-of-the-art tools in identifying context-dependent regulons. Applied to diverse spatially resolved transcriptomics platforms (Stereo-seq, STARmap, MERFISH, CosMx, Slide-seq, and 10x Visium), complex cancerous samples, and 3D datasets of developing Drosophila embryos and larvae, SpaGRN not only provides a versatile toolkit for decoding receptor-mediated spatial regulons but also reveals spatiotemporal regulatory mechanisms underlying organogenesis and inflammation.
    Keywords:  3D regulatory atlas; cellular interaction mapping; gene regulatory network; receptor; receptor-TF-target cascades; spatial autocorrelation analysis; spatially resolved transcriptomics; spatiotemporal dynamics; transcription factor
    DOI:  https://doi.org/10.1016/j.cels.2025.101243
  12. Sci Bull (Beijing). 2025 Mar 17. pii: S2095-9273(25)00288-9. [Epub ahead of print]
    An automatic annotation tool and reference database for T cell subtypes and states at single-cell resolution.
    Wen-Kang Shen, Chu-Yu Zhang, Yi-Min Gu, Tao Luo, Si-Yi Chen, Tao Yue, Gui-Yan Xie, Yu Liao, Yong Yuan, Qian Lei, An-Yuan Guo.
      T cells have various subtypes and states with different functions. However, a reference list and automated annotation tool for T cell subtypes and states are lacking, which is critical for analyzing and comparing T cells under various conditions. We constructed the largest human T cell reference, containing 1,348,268 T cells from 35 conditions and 16 tissues. We classified T cells into 33 subtypes and further stratified them into 68 categories according to subtype and state. Based on this reference, we developed a tool named STCAT to automatically annotate T cells from scRNA-seq data by hierarchical models and marker correction. The accuracy of STCAT was 28% higher than that of existing tools validated on six independent datasets, including cancer and healthy samples. Using STCAT, we consistently discovered that CD4+ Th17 cells were enriched in late-stage lung cancer patients in multiple datasets, whereas MAIT cells were prevalent in milder-stage COVID-19 patients. We also confirmed a decrease in Treg cytotoxicity in post-treatment ovarian cancer. Systematic landscape analyses of CD4+ and CD8+ T cell references revealed that CD4+ Treg cells were enriched in tumor samples and that CD8+ naive-related cells were abundant in healthy individuals. Finally, we deposited all the T cell references and annotations into a TCellAtlas (https://guolab.wchscu.cn/TCellAtlas) database, which allows users to browse T cell expression profiles and analyze customized scRNA-seq data by STCAT. In conclusion, comprehensive human T cell subtypes and states reference, automated annotation tool, and database will greatly facilitate research on T cell immunity and tumor immunology.
    Keywords:  Annotation tool; Database; Reference; T cell subtypes and states; T cells; scRNA-seq
    DOI:  https://doi.org/10.1016/j.scib.2025.02.043
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