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Immunosuppressive and metastasis-promoting matrisome proteins in pancreatic cancer: the role of galectin 4 and SERPINB5
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. (Daniel Öhlund)ORCID iD: 0000-0002-1353-316X
2022 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Immunosuppresiva och metastasfrämjande matrsomproteiner i pankreascancer : effekten av galectin-4 och SERPINB5 (Swedish)
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 [en]
pancreatic cancer, galectin 4, immunotherapy, SERPINB5, metastasis, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Oncology; Immunology; Medicine
Identifiers
URN: urn:nbn:se:umu:diva-201043ISBN: 978-91-7855-941-1 (print)ISBN: 978-91-7855-942-8 (electronic)OAI: oai:DiVA.org:umu-201043DiVA, id: diva2:1711276
Public defence
2022-12-09, Hörsal B, 9 trappor, byggnad 1D, Umeå, 13:00 (English)
Opponent
Supervisors
Part of project
Targeting Tumor-stromal Interactions in Pancreatic Cancer, Swedish Research CouncilAvailable from: 2022-11-18 Created: 2022-11-16 Last updated: 2022-11-17Bibliographically approved
List of papers
1. Cancer cell-derived matrisome proteins promote metastasis in pancreatic ductal adenocarcinoma
Open this publication in new window or tab >>Cancer cell-derived matrisome proteins promote metastasis in pancreatic ductal adenocarcinoma
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2020 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, no 7, p. 1461-1474Article in journal (Refereed) Published
Abstract [en]

The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell-derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SER-PINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell-derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell-derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. Significance: This study provides insights into the biological roles of cancer cell-derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.

Place, publisher, year, edition, pages
The American Association for Cancer Research, 2020
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-170407 (URN)10.1158/0008-5472.CAN-19-2578 (DOI)000522833600009 ()32029550 (PubMedID)2-s2.0-85082807348 (Scopus ID)
Available from: 2020-05-06 Created: 2020-05-06 Last updated: 2023-03-24Bibliographically approved
2. Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
Open this publication in new window or tab >>Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
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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
Keywords
Galectin 4, pancreatic cancer, immunosuppression, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Immunology; Medicine; Oncology
Identifiers
urn:nbn:se:umu:diva-201042 (URN)10.1158/2326-6066.CIR-21-1088 (DOI)36478037 (PubMedID)2-s2.0-85145492684 (Scopus ID)
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
3. Coordination and cooperation of immunosuppressive mechanisms in pancreatic ductal adenocarcinoma
Open this publication in new window or tab >>Coordination and cooperation of immunosuppressive mechanisms in pancreatic ductal adenocarcinoma
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The ability to evade the immune system is crucial for cancer cells to survive. In pancreatic ductal adenocarcinoma (PDAC), various mechanisms contributing to immunosuppression have been described, including the recruitment of suppressive immune cells like M2 macrophages, the expression of cell membrane attached proteins like PDL-1, or secretion of extracellular proteins inducing immune cell apoptosis. PDAC is characterized by a rich stroma, consisting of large quantities of extracellular matrix (ECM) proteins, immune cells, fibroblasts and blood vessels. Cancer cell-derived proteins deposited in the stroma can inhibit immune cell function and thereby contribute to the progression of the disease. Galectin 4 (gal 4) is highly expressed by PDAC cancer cells and is secreted into the stroma and has recently been shown to have the capacity to induce T-cell apoptosis in PDAC tumor. High levels of gal 4 is also associated to poor prognosis and reduced immune activity in PDAC patients. Here we show that sets of immunosuppressive genes form groups based on correlation of expression levels. Gal 4 gene expression correlates with other galectin family proteins, collectively clustering into a distinct immune evasion group. This cluster has negative correlation to other more classical immunosuppressive factors, such as PDL-1, CXCL12, and TGFBI, indicating that a subset of tumors mainly relies on galectins to achieve immune evasion. Conversely, tumors with low expression of gal 4 have high expression of one or more of the classical immunosuppressive factors. These results indicate that different tumors rely on different mechanisms to achieve immune evasion and emphasize the need for personalized treatment strategies when targeting immunosuppression in PDAC.  

Keywords
pancreatic adenocarcinoma, Galectin 4, immunotherapy, pancreatic cancer, immunosuppression, co-expression, combination therapy, galectin 3, galectin 9
National Category
Cancer and Oncology
Research subject
Medical Cell Biology; Oncology; Immunology
Identifiers
urn:nbn:se:umu:diva-201041 (URN)
Available from: 2022-11-16 Created: 2022-11-16 Last updated: 2022-11-16

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