Investigating the role of innate lymphoid cells in targeted radiotherapy in lung cancer

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Png Ren Jie, Shaun 

Radiotherapy is a mainstay of lung cancer treatment, and its role in regulating immune responses to promote anti-cancer response is increasingly appreciated. However, it is still not fully understood how radiotherapy modulates the immune microenvironment in lung cancer. In the lung, ILC2s are critical innate lymphocytes that modulate Type 2 immunopathology, but their role in modulating the immune response to lung cancer is not fully understood. Furthermore, it is unclear how ILC2s respond to targeted lung radiotherapy. In this thesis, I characterised the response of ILC2s to lung radiotherapy and elucidate their response alongside the general immune response in targeted radiotherapy to lung cancer. Finally, I aimed to establish a model to study the role of ILC2s in modulating the adaptive immune response in the primary lung cancer context.

I established a model of targeted lung irradiation using a preclinical treatment platform known as the Small Animal Radiation Research Platform (SARRP) and monitored immune responses. In the naïve setting, targeted lung irradiation was observed to deplete ILC2s in the long term, but this was not observed in the majority of immune cells studied. Irradiated ILC2s expressed the activation marker OX40L, though this was not accompanied by increased production of Type 2 cytokines. In the tumour setting, ILC2s also express OX40L but do not appear to contribute to anti-tumour immunity. Probing the overall immune response to targeted lung radiotherapy in the tumour context demonstrated the importance of both the innate and adaptive immune response in radiotherapy-induced anti-tumour immunity. Dendritic cells (DCs) and adaptive CD4+ and CD8+ T-cells were activated and are crucial for anti-tumour immune responses. Innate NK cells are also important as their depletion reduced the effectiveness of radiotherapy.

To study the role of ILC2s in the regulation of adaptive immune responses in cancer, I validated an inducible antigen-expressing cassette and confirmed its functionality both in vitro and in vivo. Expression of the antigen by tumour cells elicited adaptive CD4+ and CD8+ T-cell responses. I have also derived primary lung cancer cell lines to be used in combination with the cassette and demonstrate their capacity to engraft in the lung upon orthotopic implantation. Further work is needed to refine the orthotopic model of primary lung cancer, and to incorporate the cassette into the cell line. This could then be used alongside ILC2-deficient mouse models to study the role of ILC2s in modulating the adaptive immune response in lung cancer.

Halim, Tim
Innate lymphoid cells, Cancer, Radiotherapy
Awarding Institution
University of Cambridge
Cancer Research UK (S_4074)