Leiden University Scholarly Publications

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Vries, N.L. de (2022)

Novel mediators of anti-tumor immunity: dissecting intratumoral immune responses at the single-cell level

Doctoral Thesis
Immunotherapy is a highly promising treatment option for cancer. At present, only a small proportion of cancer patients benefits from immunotherapeutic interventions. There is an unmet need to understand which factors determine a patient’s response to immunotherapy as well as to develop novel immunotherapeutic approaches that address shortcomings of current immunotherapies.
In this thesis, we have performed an unprecedented characterization of immune cell subsets participating in anti-tumor responses in colorectal cancer and pancreatic ductal adenocarcinoma with different single-cell technologies. Most cancer immunology research studied the role of cytotoxic T cells in both cancer types, while a comprehensive analysis of both innate and adaptive components of cancer immunity was largely lacking. With such an approach, we demonstrated an important involvement of understudied unconventional (γδ T cells) and innate (innate lymphoid cells (ILCs)) immune effector cells in anti...Show moreImmunotherapy is a highly promising treatment option for cancer. At present, only a small proportion of cancer patients benefits from immunotherapeutic interventions. There is an unmet need to understand which factors determine a patient’s response to immunotherapy as well as to develop novel immunotherapeutic approaches that address shortcomings of current immunotherapies.
In this thesis, we have performed an unprecedented characterization of immune cell subsets participating in anti-tumor responses in colorectal cancer and pancreatic ductal adenocarcinoma with different single-cell technologies. Most cancer immunology research studied the role of cytotoxic T cells in both cancer types, while a comprehensive analysis of both innate and adaptive components of cancer immunity was largely lacking. With such an approach, we demonstrated an important involvement of understudied unconventional (γδ T cells) and innate (innate lymphoid cells (ILCs)) immune effector cells in anti-tumor immunity. These immune subsets displayed cytotoxic activity and showed potential for therapeutic exploitation. Further studies will focus on their functional characterization and potential reconversion into a therapeutic agent.
This thesis resulted from the collaboration between research groups led by Noel de Miranda (Pathology, LUMC) and Frits Koning (Immunology, LUMC), and underscores the relevance of applying single-cell technologies for the study of complex biological systems.
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Colorectal cancer
Mismatch-repair deficiency
Cancer microenvironment
Mass cytometry
Single-cell sequencing
γδ T cells
Innate lymphoid cells
Cancer immunotherapy
Immune checkpoint blockade
Pancreatic cancer
All authors
Vries, N.L. de
Supervisor
Koning, F.
Co-supervisor
Miranda, N.F.C.C. de
Committee
Staal, F.J.T.; Burg, S.H. van der; Vries; I.J.M. de; Trajanoski, Z.
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2022-10-06
ISBN (print)
9789464195460

Funding

Sponsorship
The European Commission under a MSCA-ITN award (675743: ISPIC), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant 852832), the KWF Bas Mulder Award UL (2015-7664), and the ZonMw Veni grant (916171144).