Cell, Год журнала: 2025, Номер unknown
Опубликована: Март 1, 2025
Язык: Английский
Cancer Cell, Год журнала: 2024, Номер 42(5), С. 815 - 832.e12
Опубликована: Апрель 18, 2024
Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic cues acquire hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions activating adrenomedullin paracrine signaling, thereby stimulating hyperpermeable neovasculature hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation pharmacological blockade produced restores vascular integrity, improves intratumoral concentration anti-tumor agent dabrafenib, achieves combinatorial therapeutic benefits. Increased proportion expression predictive tumor vessel hyperpermeability worse prognosis glioblastoma. Our findings highlight diversity spatial niche-steered reprogramming indicate potential therapeutics targeting normalize vasculature.
Язык: Английский
Процитировано
47
Cell, Год журнала: 2024, Номер 187(17), С. 4790 - 4811.e22
Опубликована: Июль 23, 2024
Characterizing the compositional and phenotypic characteristics of tumor-infiltrating B cells (TIBs) is important for advancing our understanding their role in cancer development. Here, we establish a comprehensive resource human by integrating single-cell RNA sequencing data from 649 patients across 19 major types. We demonstrate substantial heterogeneity total abundance subtype composition observe immunoglobulin G (IgG)-skewness antibody-secreting cell isotypes. Moreover, identify stress-response memory tumor-associated atypical (TAABs), two tumor-enriched subpopulations with prognostic potential, shared pan-cancer manner. In particular, TAABs, characterized high clonal expansion level proliferative capacity as well close interactions activated CD4 T tumors, are predictive immunotherapy response. Our integrative depicts distinct clinically relevant TIB subsets, laying foundation further exploration functional commonality diversity cancer.
Язык: Английский
Процитировано
34
Cancer Cell, Год журнала: 2024, Номер 42(7), С. 1268 - 1285.e7
Опубликована: Июль 1, 2024
Expanding the efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC) presses for a comprehensive understanding treatment responsiveness. Here, we analyze multiple sequential single-cell samples from 22 patients undergoing PD-1 to map evolution local and systemic immunity CRC patients. In tumors, identify coordinated cellular programs exhibiting distinct response associations. Specifically, exhausted T (Tex) or tumor-reactive-like CD8+ (Ttr-like) cells are closely related efficacy, Tex show correlated proportion changes with other tumor-enriched cell types following blockade. addition, reveal less-exhausted phenotype blood-associated Ttr-like tumors find that their higher abundance suggests better outcomes. Finally, major histocompatibility complex (MHC) II-related signature circulating at baseline is linked superior responses. Our study provides insights into spatiotemporal dynamics neoadjuvant CRC.
Язык: Английский
Процитировано
23
Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown
Опубликована: Янв. 9, 2025
With the dilemma of limited efficacy individual therapies, it is crucial to develop innovative combination therapy systems target complex pathogenesis cancer. In this study, we designed a nanoprodrug ISL@MIL-101-ADT facilitate synergistic delivery hydrogen sulfide (H2S) and prodrug ISL for specific eradication tumor cells with minimal toxicity maximal efficacy. The passively targeted tumors through enhanced permeation retention effects, followed by disintegration release IR780, lonidamine (LND), H2S. IR780 localizes LND mitochondria enhance therapeutic effects turn on phototherapy chemotherapy when exposed laser; H2S inhibits procancer signaling pathways mitochondrial function. vivo experiments have demonstrated that exhibits excellent pharmacokinetic properties significant inhibitory effects. Additionally, possesses outstanding photothermal fluorescence imaging capabilities. Therefore, strongly believe present herein holds great potential application in cancer therapy.
Язык: Английский
Процитировано
5
Cancer Cell, Год журнала: 2024, Номер 42(11), С. 1882 - 1897.e7
Опубликована: Окт. 17, 2024
Язык: Английский
Процитировано
10
Cancer Cell, Год журнала: 2024, Номер 42(4), С. 701 - 719.e12
Опубликована: Апрель 1, 2024
Язык: Английский
Процитировано
9
Oncogene, Год журнала: 2025, Номер unknown
Опубликована: Янв. 25, 2025
Genome-wide functional genetic screening has been widely used in the biomedicine field, which makes it possible to find a needle haystack at level. In cancer research, gene mutations are closely related tumor development, metastasis, and recurrence, use of state-of-the-art powerful technologies, such as clustered regularly interspaced short palindromic repeat (CRISPR), search for most critical genes or coding products provides us with new possibility further refine mapping provide possibilities treatment patients. The CRISPR refined atlas provided Immunotherapy, highly promising method, validated clinic, but could only meet needs small proportion Finding immunotherapy targets is key future immunotherapy. Here, we revisit application immunology from different perspectives, selection diverse vitro vivo models potential immune checkpoints potentiating CAR-T cells. data will offer fresh therapeutic clues
Язык: Английский
Процитировано
1
Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)
Опубликована: Сен. 21, 2023
Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize dynamic immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq paired scTCR/BCR-seq. exhibits inflamed-immune phenotype increased T-cell B-cell infiltration. Immunochemotherapy triggers clonal revival reinvigoration effector T cells which step determine treatment Typically, antigen-specific ISG-15+CD8+ population is highly enriched in patients, represents a transitory exhaustion state. Importantly, baseline intratumoural predict responsiveness among patients. Re-emerged clonotypes pre-existing could be found after treatment, gives rise CXCL13-expressing responsive tumours. LAG-3 retention may render into terminal state non-responsive In accordance, anti-LAG-3 therapy effectively reduce burden refractory Our results delineate distinct implication GC, leveraged optimize rational design precision immunotherapy.
Язык: Английский
Процитировано
20
Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)
Опубликована: Окт. 21, 2023
Alterations in several tripartite motif-containing (TRIM) family proteins have been implicated the pathogenesis of lung cancer. TRIM28, a member TRIM E3 ligase family, has associated with tumorigenesis, cell proliferation, and inflammation. However, little is known about TRIM28 expression its role immune microenvironment non-small cancer (NSCLC).We assessed clinical significance tissue microarrays TCGA cohorts. We investigated function syngeneic mouse tumor models, KrasLSL-G12D/+; Tp53fl/fl (KP) model, humanized mice. Immune composition was analyzed using flow cytometry immunohistochemistry.Our findings revealed positive correlation between infiltration suppressive myeloid-derived suppressor cells (MDSCs) NSCLC. Moreover, silencing enhanced efficacy anti-PD-1 immunotherapy by reshaping inflamed microenvironment. Mechanistically, we demonstrated that could physically interact receptor-interacting protein kinase 1 (RIPK1) promote K63-linked ubiquitination RIPK1, which crucial for sustaining activation NF-κB pathway. Mutagenesis domain corroborated essential activity TRIM28-mediated activation. Further experiments upregulate CXCL1 activating signaling. bind to CXCR2 on MDSCs their migration knockdown increased responsiveness therapy immunocompetent mice, characterized CD8+T tumor-infiltrating lymphocytes decreased MDSCs.The present study identified as promoter chemokine-driven recruitment through RIPK1-mediated activation, leading suppression infiltrating activated development resistance. Understanding regulation MDSC provides insights into association signaling an immunosuppressive These may inform combination therapies enhance effectiveness checkpoint blockade
Язык: Английский
Процитировано
19
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Июнь 13, 2024
Abstract Spatially resolved transcriptomics (SRT) has enabled precise dissection of tumor-microenvironment (TME) by analyzing its intracellular molecular networks and intercellular cell-cell communication (CCC). However, lacking computational exploration complicated relations between cells, genes, histological regions, severely limits the ability to interpret complex structure TME. Here, we introduce stKeep, a heterogeneous graph (HG) learning method that integrates multimodality gene-gene interactions, in unraveling TME from SRT data. stKeep leverages HG learn both cell-modules gene-modules incorporating features diverse nodes including allows for identifying finer cell-states within cell-state-specific relations, respectively. Furthermore, employs infer CCC each cell, while ensuring learned patterns are comparable across different through contrastive learning. In various cancer samples, outperforms other tools dissecting such as detecting bi-potent basal populations, neoplastic myoepithelial metastatic cells distributed tumor or leading-edge regions. Notably, identifies key transcription factors, ligands, receptors relevant disease progression, which further validated functional survival analysis independent clinical data, thereby highlighting prognostic immunotherapy applications.
Язык: Английский
Процитировано
8