Rationally designing strategies to augment checkpoint therapy in cancer

Jennings, Emma K. (2024). Rationally designing strategies to augment checkpoint therapy in cancer. University of Birmingham. Ph.D.

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Abstract

Cancer immunotherapy, such as immune checkpoint modulation (ICM), has revolutionised the treatment of cancer in recent decades. Unfortunately, only a small fraction of patients respond to the treatments, and they are associated with several immune-mediated toxicities. This project is divided into two research chapters, both aiming to rationally design a combination ICM therapy for the treatment of cancer.

Research chapter 1 focuses on designing a novel treatment for hepatocellular carcinoma (HCC), which is a type of primary liver cancer and is in the top 3 causes of cancer related deaths owing to most patients being diagnosed at advanced stage of the disease. This first research chapter uses reovirus, an oncolytic virus, to prime the tumour microenvironment for subsequent ICM therapy to treat HCC with a specific focus on the immune-mediated mechanism of oncolytic reovirus.

Research chapter 2 focuses on rationally combining antibody-mediated programmed cell death ligand 1 (PD-L1) blockade with other ICM therapy and utilises an immunogenic mouse cancer model. This chapter has a key focus on T-cell tolerance, utilising T-cell receptor (TCR) reporter mice to explore the dynamics of orphan nuclear receptor subfamily 4 (Nr4a) expression following in vitro and in vivo TCR stimulation of Tg4 transgenic mice with agonist tyrosine at position 4 [4Y]-Myelin Basic Protein (MBP) peptide. The data in research chapter 2 using these novel reporter mice reveals that anti-PD-L1 blockade leads to increased susceptibility to peptide rechallenge, lowering the T-cell activation threshold. Furthermore, anti-PD-L1 blockade in combination with OX40 agonism further boosts T-cell activation in this adaptive tolerance model. Finally, it is shown that this combination of anti-PD-L1 blockade with OX40 agonism can lead to enhanced anti-tumour effects.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Bending, David A. UNSPECIFIED UNSPECIFIED Maslowski, Kendle UNSPECIFIED UNSPECIFIED Samson, Adel UNSPECIFIED UNSPECIFIED
Licence:	Creative Commons: Attribution 4.0
College/Faculty:	Colleges (former) > College of Medical & Dental Sciences
School or Department:	Institute of Immunology and Immunotherapy
Funders:	Medical Research Council
Subjects:	Q Science > Q Science (General) Q Science > QH Natural history > QH301 Biology Q Science > QR Microbiology > QR180 Immunology Q Science > QR Microbiology > QR355 Virology
URI:	http://etheses.bham.ac.uk/id/eprint/14891

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