Bulk RNA Sequencing of Mouse Models for TLS Formation in KxPxCx Pancreatic Cancer
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PROVIDER: PRJNA1153282 | ENA |
REPOSITORIES: ENA
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Project description:The formation of tertiary lymphoid structures (TLSs) in human cancer patients is significantly correlated with prolonged survival, better prognosis, and improved responses to immune checkpoint therapy. We generated mouse models to investigate TLS formation using the KxPxCx pancreatic cancer model
2025-07-16 | GSE275836 | GEO
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:Pancreatic ductal adenocarcinoma (PDAC) is considered an immunologically cold cancer type. This perception is due to its rapid progression, strong presence of immunosuppressive cells and lack of response to current immunotherapies. However, we and others have shown that many patient PDAC tumors contain robust lymphocyte infiltration, aggregated in the form of tertiary lymphoid structures (TLS). The presence of TLS in PDAC is prognostic for long-term survival and in other cancer types, predictive of response to immunotherapy. Despite the clinical benefit to generating TLS in tumors, why they form in some PDAC patients but not others, remains unknown. The desmoplastic stroma in PDAC contributes to defective anti-tumor immunity largely due to myofibroblastic cancer associated fibroblasts (myCAF) induced by transforming growth factor-beta (TGF). Other groups have demonstrated that mesenchymal cell phenotypes with lymphoid tissue organizing properties regulate TLS formation in tumors. In order to restore effective anti-tumor immunity for PDAC patients, CAF phenotypes must be reprogrammed to support rather than restrict intratumoral immune activity. Using a lymphotoxin beta receptor (LTBR) agonist we observed induction of TLS-like aggregates in some murine PDAC tumor models, but not others. The CAF phenotypes of TLS-resistant models were predominantly myCAF while the TLS-permissive models were enriched for a VCAM1+ICAM1+ reticular-CAF (rCAF) subset. Induction of myCAF differentiation in vitro with TGF1 silenced LTBR/TNFR mediated upregulation of rCAF chemokine expression and attenuated B and T cell migration towards fibroblasts. Therapeutic TGFR1 inhibition ameliorated these effects thereby allowing LTBR agonism to repolarize rCAF phenotypic programming associated with improved lymphocyte recruitment and T cell-dependent tumor control. In patient PDAC tumors, rCAF resided next to TLS while myCAF were distally located. These data indicate that the myCAF-regulated PDAC stroma antagonizes acquisition of rCAF subsets critical for TLS formation but can be therapeutically remodeled to promote beneficial immune responses in immunosuppressive PDAC tumors.
2026-03-04 | GSE322767 | GEO
Project description:Bulk RNA Sequencing of Human PDAC: TLS-Positive vs. TLS-Negative
| PRJNA1152952 | ENA
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:The formation of tertiary lymphoid structures (TLSs) in tumors is significantly correlated with prolonged patient survival, better prognosis, and improved response to immunotherapy. To assess the tumor microenvironment associated with TLS formation, we performed bulk RNA sequencing using archived FFPE human breast cancer tissues.
2025-11-14 | GSE275955 | GEO
Project description:Pancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. Here, we report the generation of a spatial multi-omics atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning–enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning across distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that significantly associated with improved survival in PDAC patients. We identified spatial features of pathologic immune responses, including intratumoral TLS–associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.
2025-08-12 | GSE277116 | 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:Murine models of pancreatic cancer: KPC
| PRJNA836890 | ENA
Project description:ChIP using anti-TLS antibody and control to examine binding sites.
2012-03-15 | E-MEXP-3568 | biostudies-arrayexpress