Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/3152435

In Collections

This item can be found in the following collections:

Wellenstein, M.D. (2021)

Remote control: the cancer cell-intrinsic mechanisms that dictate systemic inflammation and anti-tumor immunity

Doctoral Thesis
Tumors are complex ecosystems containing not just cancer cells, but a large variety of cell types, including immune cells. Moreover, tumors have a systemic influence: they can signal long distances using soluble molecules and hijack non-neoplastic cells (such as immune cells) in distant organs for their own benefit, thus maximising their metastatic potential. The phenotype of immune cells in tumors and in systemic environments is therefore a key determinant of cancer progression and response to therapy.
This thesis aims to understand what governs the tumor-immune ecosystem. We argue that cancer-intrinsic genetic aberrations have a dominant role in determining the tumor immune contexture, as well as systemic inflammatory activation. Understanding the intricate connection between the genetics of breast cancer and anti-tumor immune responses will help develop personalised immune intervention strategies for cancer, tailored to the genetic makeup of a patient’s tumor. Furthermore,...Show moreTumors are complex ecosystems containing not just cancer cells, but a large variety of cell types, including immune cells. Moreover, tumors have a systemic influence: they can signal long distances using soluble molecules and hijack non-neoplastic cells (such as immune cells) in distant organs for their own benefit, thus maximising their metastatic potential. The phenotype of immune cells in tumors and in systemic environments is therefore a key determinant of cancer progression and response to therapy.
This thesis aims to understand what governs the tumor-immune ecosystem. We argue that cancer-intrinsic genetic aberrations have a dominant role in determining the tumor immune contexture, as well as systemic inflammatory activation. Understanding the intricate connection between the genetics of breast cancer and anti-tumor immune responses will help develop personalised immune intervention strategies for cancer, tailored to the genetic makeup of a patient’s tumor. Furthermore, we examine in detail the role of neutrophils in cancer-induced systemic inflammation, and how they influence the progression and spread of breast cancer. While tumors can be highly heterogeneous in nature, we show that neutrophils themselves also have a tremendous phenotypic diversity. Mapping this heterogeneity in neutrophil phenotypes may help to utilise these cells in cancer immunotherapy.
Show less
Tumor microenvironment
Systemic inflammation
Neutrophils
Breast cancer
Metastasis
Immunotherapy
Genetically engineered mouse models
All authors
Wellenstein, M.D.
Supervisor
Visser, K.E. de
Co-supervisor
Coffelt, S.B.
Committee
Keyser-Borst, J.G.; Dijke, P. ten, Jonkers, J.; Rheenen, J. van
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2021-03-25
ISBN (print)
9789464191226

Funding

Sponsorship
This research was financially supported by the European Research Council (ERC Consolidator InflaMet 615300), the Netherlands Organization for Scientific Research (NWO-VICI 91819616), the Dutch Cancer Society (KWF10083; KWF10623) and Oncode Institute