VU Research Portal Tumor-associated glycan structures: friend or foe in immunity to cancer? Cornelissen, L.A.M. 2019 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Cornelissen, L. A. M. (2019). Tumor-associated glycan structures: friend or foe in immunity to cancer?. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 09. Oct. 2021 Tumor-associated glycan structures: friend or foe in immunity to cancer? Lenneke A.M. Cornelissen VRIJE UNIVERSITEIT Tumor-associated glycan structures: friend or foe in immunity to cancer? ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor of Philosophy aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Geneeskunde op dinsdag 2 juli 2019 om 11.45 uur in de aula van de universiteit, De Boelelaan 1105 door Lenneke Alexandra Maria Cornelissen geboren te Boxmeer promotor: prof.dr. Y. van Kooyk copromotor: dr.ing. S.J. van Vliet Promotiecommissie Promotor Prof. Dr. Y. van Kooyk Amsterdam UMC Copromotor Dr. Ing. S.J. van Vliet Amsterdam UMC Overige leden Prof. Dr. G.J. Adema Radboudumc Dr. T.J. Boltje Radboud University Prof. Dr. K. de Visser Netherlands Cancer Institute Prof. Dr. M. van Egmond Amsterdam UMC Dr. V.L. Thijssen Amsterdam UMC Prof. Dr. M. Wuhrer Leiden University Medical Center The research presented in this thesis was performed at the Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Inflammation Institute, Amsterdam, The Netherlands. The studies described in this thesis were financially supported by Amsterdam UMC. Contents Chapter 1 Introduction Chapter 2 Transcriptional activation of fucosyltransferase (FUT) genes using the CRISPPR-dCas9-VPR technology reveals potent N-glycome alterations in colorectal cancer cells Chapter 3 A bitter sweet symphony: immune responses to altered O-glycan epitopes in cancer Chapter 4 Tn antigen expression contributes to an immune suppressive microenvironment and drives tumor growth in colorectal cancer Chapter 5 Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells Chapter 6 Disruption of sialic acid metabolism drives tumor growth through CD8+ T cell apoptosis Chapter 7 Discussion Appendices Summary Acknowledgements Curriculum vitae List of publications, grants and awards Portfolio Chapter 1 Introduction Lenneke A.M. Cornelissen The multistep development of cancer Cancer cells divide in an uncontrolled manner. Although this is probably the most fundamental trait of cancer, cancer cells must acquire more biological abnormalities to become an invasive tumor. These different characteristics of tumor development were first defined in 20001 as ‘The Hallmarks of Cancer’ and later revised and updated in 20112. At the start of development, cancer cells receive high levels of growth- promoting signals secreted by stromal cells, allowing cancer cells to proliferate in a unrestrained manner1. However, sustained cell proliferation activates cellular programs that negatively regulate cell proliferation, which cancer cells need to circumvent3. In addition, sustained cell growth triggers physiological stress that provokes counteracting responses, including cell senescence and apoptosis. Hence, cellular apoptosis functions as a natural barrier for cancer development4,5. As a consequence, next to evading growth suppressors, cancer cells need to resist cell death to maintain their chronic proliferation state. Non-malignant cells can only undergo a limited number of division cycles, controlling cell growth. Thus to sustain chronic proliferation, cancer cells must acquire replicative immortality6. But, as with normal cells, replication requires nutrients and oxygen, while metabolic waste and carbon dioxide need to be cleared. Neo-vasculature, driven by angiogenesis, is crucial for the tumor to maintain its expansion7, especially once a tumor reaches a bulky size. Moreover, local invasion and distant metastasis allows cancer cells to spread throughout the body8. Metastasis is a feature of late stage tumors in many, if not all, tumor types and reduces the probability of cure considerably. However, besides the changes in expression of cell-cell adhesion molecules, including E-Cadherin9, the main regulators of tumor invasion and metastasis are still largely undescribed and form subjects for future research. The multistep development of cancer enables malignant cells to proliferate, survive and disseminate. Nevertheless, two more hallmarks have recently been added to the revised paradigm of the ‘hallmarks of cancer’2. The first one involves the capability of the cancer cell to reprogram its cellular metabolism in order to deal with nutrients as efficiently as possible to support the enhanced cell proliferation10,11. Secondly, increasing bodies of research have proven that cancer cells evade immune destruction, by dampening the attempts of the immune system to eradicate the tumor cells12. Altogether, the combined hallmarks of cancer portray the complexity of the disease, which clarifies the challenges that come with cancer treatment. Additionally, tumors are very heterogeneous, varying between tumor types as well as within the tumor13, which urges the need to apply cancer treatment in a personalized manner. In the present thesis, we have studied two types of cancer, namely colorectal cancer and melanoma. Therefore, these two types are being introduced in more detail. Colorectal cancer Colorectal cancer (CRC) is a carcinoma of the large intestine, comprising the colon and the rectum. CRC is the third most common cancer in the Netherlands with more than 13.000 new cases every year (www.kwf.nl/kanker). The prevalence of CRC is strongly associated with age and with a western lifestyle including diet, obesity and smoking14. A rapid increase in CRC incidence and mortality is observed in South America, Asia and Eastern Europe, while numbers are declining in more developed countries including USA, Australia, New Zealand and Western Europe. This decline is likely the result of early detection and prevention programs15. Next to alcohol, red as well as processed meat consumption strongly increases the risk of CRC15,16. The exact mechanism underlying the association of meat consumption and the prevalence of CRC are not totally understood. Possible mechanisms include mutagenic and/or carcinogenic compounds 10 present in animal meat17. In addition, red meat is enriched with a monosaccharide that is absent in the human body, but is incorporated in the tissue through dietary intake. Early life exposure of red meat could trigger production of antibodies that are cross reactive against this incorporated monosaccharide. As a consequence, these antibodies can cause inflammation at a later age, which can trigger and promote tumor progression18. CRC typically starts with a polyp that progresses into a carcinoma. The staging of CRC is defined by the size and the extension of the tumor into and through the wall of the large intestine (T1, 2, 3 and 4). In addition, the presence of the cancer cells in the lymph nodes (N0, 1 or 2) and whether it has metastasized (M0 or 1) also determine the staging of CRC. For instance, a tumor, which has grown through the mucosa in the submucosa (T1) and has spread to lymph nodes (N2), but not to distance sites (M0) is categorized as CRC stage III tumor. In the Netherlands, the three year overall survival of patients with stage I and II CRC is 85-95% and 80% for stage III, however the prognosis steeply decreases when entering stage IV, leading to an overall survival of only 20%. Early detection is therefore essential to increase the overall survival rates of CRC patients Melanoma Melanoma is the rarest, but most aggressive type of skin cancer rising from melanocytes present in the skin. Melanoma is the most prevalent cancer type in the Netherlands with more than 15.000 new cases each year (www.kwf.nl/kanker). The primary cause of skin cancer is unprotected exposure to ultraviolet radiation from the sun or artificial sources. Ultraviolet radiation can damage DNA, induce gene mutations, inflammation and oxidative stress, all of which are known to promote tumorigenesis19. Protection can be achieved by either sunscreen or natural pigmentation in the skin (melanin). Melanoma staging is dependent on the thickness of the tumor as well as the presence of ulceration, mitosis, and metastasis. Till stage II the primary melanoma thickness is less than 4 mm with or without ulceration. When regional metastasis