Investigating immune responses in peritoneal adipose tissues during helminth infection and cancer metastasis

Chidomere, Chiamaka Ijeoma ORCID: 0000-0003-3118-4896 (2021). Investigating immune responses in peritoneal adipose tissues during helminth infection and cancer metastasis. University of Birmingham. Ph.D.

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Abstract

Visceral adipose tissues (VATs) within the peritoneal cavity harbour tertiary lymphoid structures known as fat associated lymphoid clusters (FALCs). These are highly vascularized; contain stromal, innate and adaptive immune cells which respond to inflammation and infection. However, FALCs are also reported to be frequent sites for metastatic tumour formation.Therefore this thesis aimed to investigate the role of VAT FALCs (namely mesenteric and omental FALCs) in mediating immune responses during helminth infection and cancer metastasis. Initial characterisation of immune cell subsets within VAT FALCs showed a marked Th2 cytokine environment which was more prominent in the omentum.Using the intestinal helminths, Heligmosomoides polygyrus and Schistosoma mansoni, we found that VAT FALCs responded to localised infections by supporting ILC2 and T cell proliferation, activation and expression of Th2 cytokines. Meanwhile, in the MC38 colon cancer model, we observed rapid and preferential localisation of tumour cells to VAT FALCs which was accompanied by the recruitment of Tregs, myeloid cells and the likely translocation of IL-33 to the stromal cell cytoplasm. However, prophylactic peritoneal inflammation reduced tumour burden and prevented tumour homing to FALCs, suggesting the manipulation of these structures to induce anti-tumour responses. Similarly, metastatic omentum from patients with high grade serous ovarian cancer was significantly infiltrated by immunosuppressive cells, with effector cells skewed towards a less activated phenotype, compared to healthy omentum. Together, these findings therefore highlight the dual, but paradoxical role of VAT FALCs during helminth infection and peritoneal cancer metastasis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):