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Mature tertiary lymphoid structures are key niches of tumor-specific immune responses in pancreatic ductal adenocarcinomas

ABSTRACT: Mature tertiary lymphoid structures are key niches of tumor-specific immune responses in pancreatic ductal adenocarcinomas

PROVIDER: PRJNA941867 | ENA |

REPOSITORIES: ENA

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Mature tertiary lymphoid structures are key niches of tumor-specific immune responses in pancreatic ductal adenocarcinomas

Project description:Objective: To better understand the immune microenvironment of pancreatic ductal adenocarcinomas (PDACs), here we explored the relevance of T and B cell compartmentalization into tertiary lymphoid structures (TLSs) for the generation of local antitumor immunity. Design: We characterized the functional states and spatial organization of PDAC-infiltrating T and B cells using single-cell RNA sequencing (scRNA-seq), flow cytometry, multicolor immunofluorescence, gene expression profiling of microdissected TLSs, as well as in vitro assays. Additionally, we performed a pan-cancer analysis of tumor-infiltrating T cells using scRNA-seq and single-cell T cell receptor sequencing (scTCR-seq) datasets from 8 cancer types. To evaluate the clinical relevance of our findings we used PDAC bulk RNA-seq data from The Cancer Genome Atlas and the PRINCE chemoimmunotherapy trial. Results: We found that a subset of PDACs harbors fully developed TLSs where B cells proliferate and differentiate to plasma cells. These mature TLSs also support T cell activity and are enriched with tumor-reactive T cells. Importantly, we showed that chronically activated, tumor-reactive T cells exposed to fibroblast-derived TGF-β may act as TLS organizers by producing the B cell chemoattractant CXCL13. Identification of highly similar subsets of clonally expanded CXCL13+ tumor-infiltrating T cells across multiple cancer types further indicated a conserved link between tumor-antigen recognition and the allocation of B cells within sheltered hubs in the tumor microenvironment. Finally, we showed that the expression of a gene signature reflecting mature TLSs was enriched in pre-treatment biopsies from PDAC patients with longer survival after receiving different chemoimmunotherapy regimens. Conclusion: We provided a framework for understanding the biological role of PDAC-associated TLSs and revealed their potential to guide the selection of patients for future immunotherapy trials.

2023-06-01 | GSE226840 | GEO

Infiltrating B cells and tertiary lymphoid structures in the TME

Project description:Single-cell profiling of infiltrating B cells and tertiary lymphoid structures in the TME of gastric adenocarcinomas

2021-11-22 | GSE188895 | GEO

Molecular and spatial analysis unveils the functional basis of tertiary lymphoid structures in Sjogren’s syndrome[scRNA-seq]

Project description:The key role of tertiary lymphoid structures in autoimmune and non-autoimmune conditions has been recently appreciated. While many of the molecular mechanisms involved in tertiary lymphoid structure formation have been identified, their cellular sources and temporal and spatial relationship remain unknown. Using single-cell RNA-sequencing, spatial transcriptomics and proteomics of minor salivary glands of patients with Sjogren’s disease and Sicca Syndrome, ex-vivo and in vivo functional studies, we construct a cellular and spatial map of key components involved in the formation and function of tertiary lymphoid structures. We confirm the presence of a fibroblast cell state and identify an undescribed pericyte/mural cell state with potential immunological functions. The identification of novel cellular properties associated with these structures and the molecular and functional interactions identified by this analysis provide key therapeutic cues for tertiary lymphoid structures associated conditions in autoimmunity and cancer.

2024-07-17 | GSE272409 | GEO

Gut-Resident IL10+CX3CR1hi Macrophages Induce Tertiary Lymphoid Structures and IgA Response in Situ

Project description:Gut resident IL10+CX3CR1hi macrophages drive development of mucosal tertiary lymphoid structures that serve as ectopic site of the IgA response to enteric infection.

2020-04-17 | GSE121471 | GEO

Molecular and spatial analysis unveils the functional basis of tertiary lymphoid structures in Sjogren’s syndrome[bulk RNA-seq]

2024-07-17 | GSE272410 | GEO

Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas

Project description:Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas

| PRJNA931755 | ENA

RNA tertiary structure and conformational dynamics revealed by BASH MaP

Project description:The functional effects of an RNA can arise from complex three-dimensional folds known as tertiary structures. However, predicting the tertiary structure of an RNA and whether an RNA adopts distinct tertiary conformations remains challenging. To address this, we developed BASH MaP, a single-molecule dimethyl sulfate (DMS) footprinting method and DAGGER, a computational pipeline, to identify alternative tertiary structures adopted by different molecules of RNA. BASH MaP utilizes potassium borohydride to reveal the chemical accessibility of the N7 position of guanosine, a key mediator of tertiary structures. We used BASH MaP to identify diverse conformational states and dynamics of RNA G-quadruplexes, an important RNA tertiary motif, in vitro and in cells. BASH MaP and DAGGER analysis of the fluorogenic aptamer Spinach reveals that it adopts alternative tertiary conformations which determine its fluorescence states. BASH MaP thus provides an approach for structural analysis of RNA by revealing previously undetectable tertiary structures.

2024-10-14 | GSE271825 | GEO

Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [RNA-Seq]

Project description:Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [RNA-Seq]

| PRJNA934450 | ENA

Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [Cut&Tag]

Project description:Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [Cut&Tag]

| PRJNA865693 | ENA

Infiltrating B cells and tertiary lymphoid structures in the TME

Project description:Infiltrating B cells and tertiary lymphoid structures in the TME

| PRJNA780577 | ENA