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Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences. (Daniel Öhlund)ORCID iD: 0000-0002-1353-316X
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences. (Daniel Öhlund)
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences. (Daniel Öhlund)
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. (Niklas Arnberg)
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2023 (English)In: Cancer immunology research, ISSN 2326-6066, Vol. 11, no 1, p. 72-92Article in journal (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell produced protein deposited into the ECM of PDAC tumors and detected high circulating levels of gal 4 in PDAC patients. In orthotopic transplantation experiments we observed increased infiltration of T-cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. Furthermore, by performing single-cell RNA-sequencing we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression was associated with higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T-cells and antigen presenting dendritic cells in tumors with reduced gal 4 expression. Using a co-culture system, we observed that extracellular gal 4 induced apoptosis in T-cells by binding N-glycosylation residues on CD3 epsilon/delta. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC. 

Place, publisher, year, edition, pages
American Association for Cancer Research , 2023. Vol. 11, no 1, p. 72-92
Keywords [en]
Galectin 4, pancreatic cancer, immunosuppression, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Immunology; Medicine; Oncology
Identifiers
URN: urn:nbn:se:umu:diva-201042DOI: 10.1158/2326-6066.CIR-21-1088PubMedID: 36478037Scopus ID: 2-s2.0-85145492684OAI: oai:DiVA.org:umu-201042DiVA, id: diva2:1711212
Part of project
Targeting Tumor-stromal Interactions in Pancreatic Cancer, Swedish Research Council
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), PT2015-6432Swedish Cancer Society, AMP17-877, LP18-2202, LP20-2257, LP 21-2298Swedish Research Council, 2017-01531The Kempe Foundations, JCK-1301, SMK-1765Swedish Society of Medicine, SLS-890521, SLS-786661, SLS-691681, SLS-591551Västerbotten County Council, RV-930167, VLL-643451, VLL-832001Sjöberg FoundationKnut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, CAN 2017/332, CAN 2017/827, 20 1339 PjFSwedish Cancer Society, AMP-18-919Knut and Alice Wallenberg Foundation
Note

Originally included in thesis in manuscript form. 

Available from: 2022-11-16 Created: 2022-11-16 Last updated: 2023-10-18Bibliographically approved
In thesis
1. Immunosuppressive and metastasis-promoting matrisome proteins in pancreatic cancer: the role of galectin 4 and SERPINB5
Open this publication in new window or tab >>Immunosuppressive and metastasis-promoting matrisome proteins in pancreatic cancer: the role of galectin 4 and SERPINB5
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Immunosuppresiva och metastasfrämjande matrsomproteiner i pankreascancer : effekten av galectin-4 och SERPINB5
Abstract [en]

In Sweden 1200-1300 people are diagnosed with pancreatic ductal adenocarcinoma (PDAC) every year. Late diagnosis, together with poor treatment response and resistance to checkpoint inhibitor immunotherapy, contributes to the poor prognosis of the disease. 

PDAC is characterized by abundant deposits of extracellular matrix, which mainly includes structural proteins including collagens, proteoglycans, cell-binding glycoproteins, carbohydrates, and secreted proteins, all constituting the matrisome of the tumor. The matrisome protects cancer cells and affects the outcome. Several highly expressed matrisome proteins are involved in oncogenesis, including the processes of immunosuppression and metastasis formation, therefore contributing to the poor prognosis. In this thesis the pathophysiological role of several matrisome proteins in PDAC tumor progression was studied. Unbiased analysis of matrisome proteins in PDAC tumors revealed increased levels of cancer cell-derived secreted proteins compared to normal healthy control tissue. Subsequently, differentially expressed candidate proteins, with known cellular functions in other disease but hitherto uncharacterized role in PDAC progression, were selected.

Serine protease inhibitor clade B member 5 (SERPINB5), agrin, and cystatin B (CSTB), were selected for the study described in paper I based on their known roles in the metastasis formation process in other types of cancers. SERPINB5, agrin and CSTB were found to increase metastasis in models of PDAC by affecting epithelial to mesenchymal transition, ECM degradation and extravasation. In PDAC tumors, high levels of extracellular SERPINB5 correlated to reduced overall survival.  

Galectin 4 (Gal 4) was selected for the study described in paper II based on its known immunosuppressive effects. Gal 4 is highly expressed in PDAC and was found to inhibit T cell infiltration and induce apoptosis in CD8+ T cells by binding to CD3 on the surface of T cells. Gal 4 was associated with better survival in PDAC patients and correlated to higher activation and cytolytic effect of CD8+ T cells.

The relation between gal 4 and other immunosuppressive proteins was studied in paper III. Analysis of available datasets revealed that gal 4 expression correlates with other cancer cell-derived immunosuppressive proteins of the galectin family, galectin 3 and galectin 9, while negatively correlating with the stroma-derived factors galectin-1 and TGFBI.

Findings in this thesis show that targeting of matrisome proteins in PDAC can be a promising therapy strategy. Blocking extracellular SERPINB5 could result in reduced metastasis and increased survival. Blocking intracellular gal 4 could increase anti-tumor immunity and synergize with checkpoint inhibition therapy.

The identified co-expression and coregulation of different immunosuppressive proteins indicate that different tumors can be classified based on their predominant immunosuppressive mechanisms. Following this classification in individual patients, combinations of therapies against different immunosuppressive mechanisms could represent a promising strategy to introduce effective immunotherapies for PDAC patients.  

Place, publisher, year, edition, pages
Umeå: Umeå University, 2022. p. 87
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2207
Keywords
pancreatic cancer, galectin 4, immunotherapy, SERPINB5, metastasis, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Oncology; Immunology; Medicine
Identifiers
urn:nbn:se:umu:diva-201043 (URN)978-91-7855-941-1 (ISBN)978-91-7855-942-8 (ISBN)
Public defence
2022-12-09, Hörsal B, 9 trappor, byggnad 1D, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2022-11-18 Created: 2022-11-16 Last updated: 2022-11-17Bibliographically approved
2. The identification and functional evaluation of novel cancer-associated fibroblast subtypes and matrisome proteins in pancreatic cancer
Open this publication in new window or tab >>The identification and functional evaluation of novel cancer-associated fibroblast subtypes and matrisome proteins in pancreatic cancer
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Identifiering och funktionell utvärdering av nya cancer-associerade fibroblast-subtyper och matrisomeproteiner i pankreascancer
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by an extensive desmoplastic stroma. The stroma is the site of intricate communication between malignant cells and their surrounding environment. This tissue microenvironment (TME) is populated by a heterogenous mixture of cell types and extracellular matrix proteins. Distinct stromal elements confer tumour-restraining or tumour-promoting influences on tumorigenesis. Characterizing stromal composition therefore represents an opportunity to identify candidates for therapeutic intervention to facilitate improved clinical outcomes. In this thesis we identify galectin-4 as an extracellular matrix protein which is upregulated in PDAC. We find that galectin-4 exerts a pro-tumorigenic influence in PDAC through promoting immune suppression, highlighting its potential as a novel therapeutic target. We subsequently provide a comprehensive characterization of mesenchymal cell diversity in PDAC including cancer-associated fibroblasts (CAFs) which represent one of the dominant stromal cellular components. We identify inflammatory CAF (iCAF) and myofibroblastic CAF (myCAF) subtypes in addition to defining a novel interferon-response CAF (ifCAF) subtype. In addition, we demonstrate that pancreatic stellate cells (PSCs) are capable of forming iCAFs, myCAFs and ifCAFs in response to tumour-derived signals using an organoid-based co-culture model and define biological pathways regulating CAF subtype formation. We then perform a high-throughput drug-screen using this co-culture model to identify compounds which can suppress tumour growth indirectly through modifying CAFs. One such compound is GNF-5 which we show can suppress cancer cell proliferation indirectly through manipulating CAF phenotype. Taken together, this thesis augments our understanding of the composition of the PDAC stroma and identifies potential therapeutic targets as well as developing an approach to discover drugs which yield a therapeutic benefit through targeting the PDAC stroma.   

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 122
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2259
Keywords
Cancer-associated fibroblast (CAF), Single-cell RNA sequencing (scRNAseq), Pancreatic ductal adenocarcinoma (PDAC), Tumor microenvironment (TME), Extracellular matrix (ECM), Organoid-based co-culture model, Drug-screen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-215330 (URN)9789180701747 (ISBN)9789180701754 (ISBN)
Public defence
2023-11-17, Betula, 6M, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2023-10-26 Created: 2023-10-18 Last updated: 2023-10-19Bibliographically approved

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Lidström, TommyCumming, JoshuaGaur, RahulFrängsmyr, LarsFranklin, OskarForsell, Mattias N. E.Arnberg, NiklasDongre, MiteshPatthey, CedricÖhlund, Daniel

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Wallenberg Centre for Molecular Medicine at Umeå University (WCMM)Department of Radiation SciencesDepartment of Clinical MicrobiologyDepartment of Surgical and Perioperative Sciences
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