Targeting fibroblast activation protein with chimeric antigen receptor macrophages

Biochemical Pharmacology, Год журнала: 2024, Номер 230, С. 116604 - 116604

Опубликована: Ноя. 1, 2024

Язык: Английский

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scRNA-seq characterizing the heterogeneity of fibroblasts in breast cancer reveals a novel subtype SFRP4+ CAF that inhibits migration and predicts prognosis

Frontiers in Oncology, Год журнала: 2024, Номер 14

Опубликована: Апрель 15, 2024

Introduction Cancer-associated fibroblasts (CAFs) are a diverse group of cells that significantly impact the tumor microenvironment and therapeutic responses in breast cancer (BC). Despite their importance, comprehensive profile CAFs BC remains to be fully elucidated. Methods To address this gap, we utilized single-cell RNA sequencing (scRNA-seq) delineate CAF landscape within 14 normal-tumor paired samples. We further corroborated our findings by analyzing several public datasets, thereby validating newly identified subtype. Additionally, conducted coculture experiments with assess functional implications Results Our scRNA-seq analysis unveiled eight distinct subtypes across five six adjacent normal tissue Notably, discovered novel subtype, designated as SFRP4+ CAFs, which was predominantly observed tissues. The presence substantiated two independent datasets spatial transcriptomics dataset. Functionally, were found impede cell migration epithelial-mesenchymal transition (EMT) process secreting SFRP4, modulating WNT signaling pathway. Furthermore, established elevated expression levels markers correlate improved survival outcomes patients, yet paradoxically, they predict diminished response neoadjuvant chemotherapy cases triple-negative cancer. Conclusion This investigation sheds light on heterogeneity introduces subtype hinders migration. discovery holds promise potential biomarker for refined prognostic assessment intervention BC.

Язык: Английский

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Nano-enhanced immunity: A bibliometric analysis of nanoparticles in vaccine adjuvant research

Human Vaccines & Immunotherapeutics, Год журнала: 2024, Номер 20(1)

Опубликована: Ноя. 14, 2024

This study analyzed the growth, collaboration, citation trends, and emerging topics in nanoparticle-based vaccine adjuvant research (NVAR) from 1977 to 2023, using data Scopus database. The field showed a steady growth rate of 7.53% per year. Leading researchers Jaafari, M.R. Alving, C.R. contributed significantly field, with 24.22% publications 38.92% total citations coming United States. International collaboration was very strong, particularly between US, UK, Germany, China, France. Key include nanoparticles, immunotherapy, COVID-19, vaccines focus on SARS-CoV-2 malaria. Emerging adjuvants, mRNA, neutralizing antibodies. emphasizes importance ongoing interdisciplinary efforts advance NVAR.

Язык: Английский

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Development of FAP-targeted theranostics discovered by next-generation sequencing-augmented mining of a novel immunized VNAR library

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 14, 2025

Cancer-associated fibroblasts (CAFs) in the stroma of solid tumors promote an immunosuppressive tumor microenvironment (TME) that drives resistance to therapies. The expression protease fibroblast activation protein (FAP) on surface CAFs has made FAP a target for development therapies dampen immunosuppression. Relatively few biologics have been developed and none exploit unique engagement properties Variable New Antigen Receptors (VNARs) from shark antibodies. As smallest binding domain nature, VNARs cleverage geometries recognize epitopes conventional antibodies cannot. By directly immunizing nurse with FAP, we created large anti-FAP VNAR phage display library. This library allowed us identify suite through traditional biopanning also by silico approach did not require any prior affinity-based enrichment vitro . We investigated four VNAR-Fc fusion proteins theranostic found all recognized high affinity were rapidly internalized FAP-positive cells. result, constructs effective antibody-drug conjugates able localize xenografts vivo Our findings establish as versatile platform could yield innovative cancer targeting TME.

Язык: Английский

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Advances in engineered T cell immunotherapy for autoimmune and other non-oncological diseases

Biomarker Research, Год журнала: 2025, Номер 13(1)

Опубликована: Фев. 4, 2025

Abstract Adoptive immunotherapy using engineered T cells expressing chimeric antigen receptors has shown remarkable success in treating patients with hematological malignancies. However, realizing broader therapeutic applications of other diseases requires further exploration clinical investigations. In this review, we highlight recent advances the engineering non-oncology areas, including autoimmune and inflammatory diseases, infections, fibrosis, hemophilia, aging. Chimeric receptor good outcomes but many challenges remain improving its safety efficacy expanding application to treatment non-oncological diseases.

Язык: Английский

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Anlotinib may have a therapeutic effect on papillary craniopharyngiomas without the BRAFv600e mutation

Acta Neuropathologica Communications, Год журнала: 2025, Номер 13(1)

Опубликована: Март 3, 2025

Although successful treatment of papillary craniopharyngiomas (PCPs) with BRAFv600e inhibitors has been reported in clinical trials, studies have shown that approximately 10% PCPs lack the mutation and may not be significantly effective against these tumors. However, no focused specifically on BRAFv600e− PCPs. Spatial transcriptome sequencing was performed calcified PCP tissue to identify novel subtypes cells. The findings were validated via pathological methods 51 samples. Primary cells from patients BRAFv600e+ isolated then injected into brains nude mice stereotactic surgery establish a stable mouse model human-originated PCP. Model treated vemurafenib, BRAF inhibitor, anlotinib, an angiogenesis inhibitor. BRAFv600e−PCP anlotinib phase 1 trial. Changes tumors monitored methods, CT MRI. Most negative for mutation, confirmed vemurafenib significant therapeutic effect verified that, Two participated trial received therapy; their disappeared after 3 months therapy did recur within 24 follow-up stopping treatment. are characterized by calcification do respond inhibitor which effect.

Язык: Английский

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Enhanced efficacy of dual chimeric antigen receptor-T cells targeting programmed death-ligand 1 and cancer-associated fibroblasts in colorectal cancer in vitro

CytoJournal, Год журнала: 2025, Номер 22, С. 29 - 29

Опубликована: Март 6, 2025

Colorectal cancer (CRC) presents significant treatment challenges, including immune evasion and tumor microenvironment (TME) suppression. Chimeric antigen receptor (CAR) T-cell therapy has shown promise in hematologic malignancies, but its effectiveness against solid tumors is hampered by the detrimental effects of TME. This article aims to explore potential bispecific CAR T cells targeting programmed death-ligand 1 (PD-L1) cancer-associated fibroblasts (CAFs) CRC treatment. Dual-targeted CAR-T PD-L1 CAF were engineered using GV400 lentiviral vector. Programmed death-1 (PD-1)/nanobody (Nb) fibroblast activation protein (FAP)/Nb-encoding vectors generated, produced through a three-plasmid system 293T cells. Human peripheral blood mononuclear (PBMCs) separated, transduced with these vectors, then expanded. Functional characterization was performed enzyme-linked immunosorbent assay (ELISA), Western blot analysis, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, cell counting kit-8 (CCK-8) assay. Migration invasion assays conducted Transwell chambers assess ability FAP-PD-1/Nb migrate toward invade extracellular matrix. We developed dual-targeted incorporating Nbs, which continuously secreted PD-1/Nb. confirmed PD-1/Nb expression cells, no untreated (UTD) group (P < 0.01). Flow cytometry showed significantly higher cluster differentiation (CD)25 CD69 upon stimulation FAP-positive target compared other groups TUNEL, CCK-8 revealed that exhibited superior cytotoxicity proliferation inhibition HCT116 ELISA demonstrated increased interferon-gamma necrosis factor-alpha levels reduced interleukin-10 0.01), suggesting enhanced cytokine modulation antitumor immunity. Compared single-target UTD, notably Matrigel penetration Safety tests minimal normal PBMCs, indicating favorable safety. study successfully their activity immunomodulatory on novel therapeutic strategy established technology for CRC.

Язык: Английский

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Fibroblasts in immune responses, inflammatory diseases and therapeutic implications

Nature Reviews Rheumatology, Год журнала: 2025, Номер unknown

Опубликована: Май 14, 2025

Язык: Английский

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Characterization of cancer‐associated fibroblasts and their spatial architecture reveals heterogeneity and survival associations in classic Hodgkin lymphoma

HemaSphere, Год журнала: 2025, Номер 9(5)

Опубликована: Май 1, 2025

Abstract Cancer‐associated fibroblasts (CAFs) are a heterogeneous population of stromal cells, which modulate the immune system and can have both pro‐ anti‐tumorigenic effects. In classic Hodgkin lymphoma (cHL), role CAFs has remained largely undefined. We applied multiplexed immunofluorescence imaging spatial analysis on tumor samples from two independent cHL patient cohorts ( n = 131 148) to study their interactions with Reed–Sternberg (HRS) microenvironment (TME) cells at single‐cell resolution. show that higher proportions associated favorable outcomes, clinical covariables. contrast, subset CD45 + strong fibroblast‐activation protein positivity, classified as macrophages, was less abundant in nodular sclerosis subtype worse outcomes. Neighborhood allowed for identification colocalization or regional exclusion phenotypically defined cell types recurrent cellular neighborhoods. Despite positive impact CAF survival, patients enrichment platelet‐derived growth factor receptor beta (PDGFRB)‐positive vicinity HRS had survival cohorts, determinants. Our findings distinguish various subsets macrophages impacting underscore importance arrangements TME.

Язык: Английский

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CAR-T Cell Therapy: Advances in Digestive system malignant tumors

Deleted Journal, Год журнала: 2024, Номер 32(4), С. 200872 - 200872

Опубликована: Сен. 10, 2024

Malignant tumors of the digestive system have had a notoriously dismal prognosis throughout history. Immunotherapy, radiotherapy, surgery, and chemotherapy are primary therapeutic approaches for cancers. The rate recurrence metastasis, nevertheless, remains elevated. As one immunotherapies, chimeric antigen receptor T cell (CAR-T) therapy has demonstrated promising antitumor effect in hematologic cancer. Despite undergoing numerous clinical trials, ineffective adverse effects CAR-T treatment cancers continue to impede its translation. It is necessary surmount restricted options targeting proteins, obstacles that infiltration into solid tumors, limited survival time

Язык: Английский

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