Immunosuppression in breast cancer: a closer look at regulatory T cells

Kos, K. (2023)

Doctoral Thesis

The immune system plays a dual role in cancer development. Besides the potential to eliminate cancer cells, immunoregulatory mechanisms exist that counteract anti-tumor immunity.

Research in this thesis focusses on the role of regulatory T cells (Tregs), a type of adaptive immune cell that plays a major role in tumor-associated immunosuppression. Specifically, the role of Tregs was investigated during the development of primary- and metastatic breast cancer, and in the context of novel immunotherapeutics. This was done by using advanced genetically engineered mouse models that recapitulate human breast cancer.
The results in this thesis describe that breast tumors are, already early in their development, able to mobilise Tregs in the tumor-draining lymph nodes, thereby creating a local immunosuppressive niche leading to increased lymph node metastasis. In addition, it was found that the immunotherapeutic treatments anti-PD1 and anti-CTLA4 inadvertently activate Tregs, resulting in a diminished efficacy of this treatment in mice bearing breast tumors. Finally, we describe a mechanism by which intratumoral macrophages are critical promote the intratumoral accumulation of Tregs in breast tumors.
Insights from this thesis may eventually contribute to the development of therapeutic applications that are aimed at overcoming immunoregulatory mechanisms in breast cancer.

• Tumor immunology
• Immunosuppression
• Breast cancer
• Regulatory T cells
• Metastasis
• Immunotherapy

• All authors: Kos, K.
• Supervisor: Visser, K.E. de
• Co-supervisor: Borst, J.G.
• Committee: Ossendorp, F.A.; Burg, S.H. van der; Yazdanbakhsh, M.; Gruijl, T.D. de; Akkari, L.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2023-01-11
• ISBN (print): 9789464196542
• Sponsorship: NWO OOA Diamond grant; KWF; Oncode institute