Bulk RNA Sequencing of Mouse Models for TLS Formation in KxPxCx Pancreatic Cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275836 | GEO | 2025/07/16
REPOSITORIES: GEO
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Project description:The formation of tertiary lymphoid structures (TLSs) in tumors is significantly correlated with prolonged patient survival, better prognosis, and improved response to immunotherapy. Understanding the tumor microenvironments involved in TLS formation is crucial. This bulk RNA sequencing study utilized archived FFPE samples from PDAC patients to reveal gene expression profiles in tumors with TLS formation.
2025-07-16 | GSE275766 | GEO
Project description:Ovarian cancer is insensitive to immunotherapy and has a high mortality rate. CDK4/6 inhibitors (CDK4/6i) regulate the tumor microenvironment and play an antitumor role. Our previous research demonstrated that lymphocyte aggregation (tertiary lymphoid structures, TLS) was observed after CDK4/6i treatment. This may explain the synergistic action of CDK4/6i with the anti-PD1 antibody. However, the key mechanism by which CDK4/6i promotes TLS formation has not been elucidated. We examine the link between TLS and prognosis. Animal models and high-throughput sequencing were used to explore the potential mechanism by which CDK4/6i promotes TLS formation. Our results showed the presence of TLSs was associated with a favorable prognosis for ovarian cancer. CDK4/6i promoted TLS formation and enhanced the immunotherapeutic effect of the anti-PD1 antibody. The potential mechanism of CDK4/6i affecting the formation of TLS may be through modulating SCD1 and its regulatory molecules ATF3 and CCL4. Our findings provide a theoretical basis for the application of CDK4/6i in ovarian cancer.
2023-10-12 | GSE234106 | GEO
Project description:Background and aims: Tertiary lymphoid structures (TLSs) are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy. In liver cancer, TLSs have been reported to be pro-tumorigenic as they harbor tumor progenitor cells and nurture their growth. The processes involved in TLS development and the acquisition of a pro- or anti-tumorigenic phenotype in cancer are largely unknown. RORc expressing immune cells have been previously implicated in TLS formation, however, their role in TLS development in the context of inflammation-associated liver cancer remains unexplored. Methods: IKKβ(EE)Hep mice, exhibiting chronic liver inflammation and TLS formation followed by liver cancer, were crossed with RORc knockout mice to explore the effect of RORc on TLS and tumor formation. Transcriptional, proteomic and immunohistochemical techniques were used to analyze TLS phenotypes. CD4, CD8 and B cell depletions were used to analyze their contribution to liver TLS and tumor formation. Results: RORc expressing cells were detected within TLSs of both human patients and mice which develop intrahepatic cholangiocarcinoma. In mice, RORc expressing cells negatively regulate TLS formation, since in their absence TLSs form in excess. CD4 cells are essential for liver TLS formation whereas B cells are required for TLS formation specifically in the absence of RORc expressing cells. Importantly, in chronically inflamed livers lacking RORc expressing cells, TLSs become anti-tumorigenic, resulting in reduced tumor load. Comparing liver pro- and anti-tumorigenic TLSs, revealed enrichment of exhausted CD8 cells that retained effector functions, as well as germinal center B cells and plasma cells in anti-tumorigenic TLSs. Cell depletion experiments revealed a role mainly for B cells in limiting tumor development, possibly via tumor-directed antibodies. Conclusions: RORc expressing cells negatively regulate B cell responses, and facilitate the pro-tumorigenic functions of hepatic TLSs.
2024-12-01 | GSE277327 | GEO
Project description:Tertiary lymphoid structures (TLSs) are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy. In liver cancer, TLSs have been reported to be pro-tumorigenic as they harbor tumor progenitor cells and nurture their growth. The processes involved in TLS development and acquisition of pro- or anti-tumorigenic phenotype in cancer are largely unknown. RORc expressing immune cells have been previously implicated in TLS formation, however we find that they are not necessary for TLS neogenesis in the context of liver inflammation. On the contrary, RORc expressing cells negatively regulate TLS formation, since in their absence TLSs form in excess. CD4 cells are essential for liver TLS formation whereas B cells are required for TLS formation specifically in the absence of RORc expressing cells. Importantly, in chronically inflamed livers lacking RORc expressing cells, TLSs become anti-tumorigenic, resulting in reduced tumor load. Comparing liver pro- and anti-tumorigenic TLSs by transcriptional, proteomic and immunohistochemical analyses, revealed enrichment of exhausted CD8 cells that retained effector functions as well as germinal center B cells and plasma cells in anti-tumorigenic TLSs. Cell depletion experiments revealed a role mainly for B cells in limiting tumor development, possibly via tumor directed antibodies. Thus, RORc expressing cells negatively regulate B cell responses, and facilitate the pro-tumorigenic functions of hepatic TLSs.
2024-12-01 | GSE255446 | GEO
Project description:The outcome of immune checkpoint blockade (ICB) therapy largely hinges on the antitumor immune response of tertiary lymphoid structures (TLSs), but the driver factors behind tumor TLS formation remain poorly understood. Through integrated analysis of spatial and pan-cancer single-cell transcriptomics, we reveal the characteristics of TLSs in nasopharyngeal carcinoma (NPC) and identify a subset of interferon responsive high endothelial venules (IFN-HEVs) that is responsible for the emergence of tumor-specific chemokines, especially CXCL9. Functionally, IFN-HEVs facilitate the recruitment of CD4+ T cells into TLSs via the CXCL9-CXCR3 axis. IFN-HEV-related phenotypes are strongly correlated with positive prognostic outcomes and better responses to ICB therapy. Leveraging these phenotypes, we develop a pretreatment CXCL9-TLS Response-predictive scoring system (CTRscore) to forecast the efficacy of ICB therapy and validate its predictive efficiency in three independent NPC cohorts. Our study provides biological and functional insights into the IFN-HEVs in tumor TLSs, highlighting their potential role in the development of biomarkers and predictors for the success of ICB therapy.
2025-05-02 | GSE289272 | GEO
Project description:The presence of B cells in tumors have been recently reported to predict the better prognosis of patients with cancer. B cells were found primarily in so-called tertiary lymphoid structures (TLSs) in tumor. TLSs are ectopic lymphoid aggregates that form at sites of micro-secondary lymphoid organs, including a B cell follicle with a network of follicular dendritic cells (FDCs) surrounded by T cell zone composed of CD4+ T follicular helper (Tfh) cells and CD8+ T cells and high endothelial venules (HEVs). The presence of TLS is associated with positive outcomes in several human malignancie and More importantly, TLSs enriched in B cells have been proven beneficial for response to ICB in multiple types of cancer. Here, we establish tobacco-associated HNSCC mouse model with TLS enrichment by overexpression of LIGHT in tumor to evaluate the TLS influence in HPV- HNSCC and immunotherapy in HPV- HNSCC.
2022-03-03 | GSE197559 | GEO
Project description:The discovery of tertiary lymphoid structures (TLS) within the tumor tissues provides a promising avenue to promote the response rate of cancer immunotherapy. Yet, the lack of effective strategies to promote TLS formation poses a substantial obstacle. Thus, the exploration of potential inducers for TLS formation is of great interest but remains challenging. Here, inspired by the mechanism of artificially cultivated pearls, a covalent organic frameworks (COFs) was employed to promote the formation of TLS. Single-cell sequencing analysis revealed that this was achieved by promoting the cytokine hypersecretion to facilitate the maturation, proliferation, and migration of T and B cells, critical for trigger TLS formation. Furthermore, the high efficacy of COF-mediated phototherapy in inducing TLS formation was validated in both the MC38 and 4MOSC1 tumor models. Moreover, an efficient synergism between COF-mediated phototherapy and αCTLA-4 was observed, which was able to effectively eradicate both primary and distant tumors, and inhibit tumor recurrence. This study underscores a new approach of boosting cancer immunotherapy through COF triggered TLS formation.
2024-10-31 | GSE268619 | GEO
Project description:Tertiary lymphoid structures (TLS) play a pivotal role in sustaining chronic inflammation within autoimmune diseases and tumors by fostering crucial immune cell interactions. While much is known about TLS linked to mucosal epithelium, their formation in the skin epithelium and the supporting microenvironment remains unclear. Using multiomics, we uncovered the presence of TLSs in a severe chronic inflammatory skin disease, Hidradenitis Suppurativa (HS), and showed that lymphocyte proliferation exclusively occurs in TLSs, predominantly located in adjacent to the unique epithelialized tunnels in lesional skin. Notably, we found extensive clonal expansion of plasma cells generating antibodies specific to HS lesional keratinocytes across different patients, alongside the proliferation of Tfh, Treg, and pathogenic T cells (IL17A+ and IFNG+). Additionally, we identified two distinct skin fibroblast populations with transcriptional signatures resembling stromal cells in secondary lymphoid organs (SLO), expressing CXCL13 or CCL19, in response to immune cytokines. Employing a microfluidic system to mimic TLSs-on-a-chip, we demonstrated that HS lesional fibroblasts are critical in orchestrating lymphocyte aggregation and proliferation, which involve TNFα-CXCL13 and TNFα-CCL19 feedback loops with B and T cells, respectively. Furthermore, our study revealed that early TNFα blockade effectively suppresses lymphocyte aggregation, but not after aggregates are formed, underscoring the critical role of TNFα during the initiation of the lymphoid aggregation. Through dissecting the intricate network interactions between immune and mesenchymal cells within the HS lesion, our work revealed the crucial mechanism sustaining chronicity in Hidradenitis Suppurativa and potentially other autoimmune diseases.
2024-12-13 | GSE158955 | GEO
Project description:Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade (ICB), but understanding of their clinical significance and the circumstances of their resolution remains incomplete. Here, we found that in hepatocellular carcinoma (HCC) treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse free survival. In areas of tumor regression, we further identified a non-canonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions, and increased expression of T cell memory markers. Collectively, these data suggest that TLS may serve be both a prognostic and predictive marker of response to immunotherapy in HCC and suggest a functional role for late-stage TLS T cell memory formation after elimination of viable tumor.
2024-09-13 | GSE272346 | GEO
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