One bite at a time: multiomic unveiling of monocyte trogocytosis of tumour cells

Thesis

Monocytes are innate immune cells recognized for the plasticity in their response to cancer. They undergo tumour-promoting alterations and have been linked to worse clinical outcomes including poor response to immunotherapy in patients with more prevalent solid tumours. We have found trogocytosis, a poorly understood cell-cell interaction pathway, to be a mode of monocyte-tumour cell communication that impacts myeloid cell activation. Key regulators governing monocyte-mediated tumour-cell trogocytosis and its effects on the balance of immune suppression versus activation are yet to be characterized. In addition, most of what is currently understood of myeloid cell biology, including trogocytic interactions, has largely been unexplored in rare solid tumours like sarcomas.

Here, we establish a baseline understanding of myeloid biology in sarcomas by 1) exploring existing transcriptomic datasets to evaluate associations of myeloid cell state with patient outcomes, and 2) assessing phenotypic changes in patient circulating myeloid populations. Subsequently, we conduct more specific functional assessment of monocytic populations through the implementation of -omic techniques to map the drivers of tumour-cell trogocytosis by monocytes and its resulting signalling cascade. To do so, we 1) establish in vitro assessment of features of monocyte trogocytosis of tumour cells, 2) identify key genes driving monocyte trogocytosis and 3) determine transcriptional signatures following monocyte trogocytosis.

These studies provide a platform for myeloid-focused studies, generate a deeper understanding of myeloid function in cancer progression, as well as identify potential new targets to inform immunotherapy approaches in paediatric patients with solid tumours.

Authors: Contreras Burrola, CF

• DOI: 10.5287/ora-vj8qzk62g
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: sarcomas; trogocytosis; paediatric malignancies; myeloid biology; tumour immune microenvironment
• Subjects: Immune response; Cancer in children; Monocytes