Coelho, MA; (2017) Oncogenic RAS Signalling Promotes Tumour Immunoresistance by Stabilising PD-L1 mRNA. Doctoral thesis , UCL (University College London).

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Abstract

The immunosuppressive molecule PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. Recent clinical trials of immunotherapies in cancer using antibodies targeting PD-L1 and its receptor PD-1 have led to promising responses in a subset of patients. These results emphasise the pressing need for biomarkers of patient response and means to increase the number of patients that benefit from these immunotherapies. One potential biomarker is PD-L1 on tumour cells, although the relative importance of the tumour microenvironment and cellintrinsic signalling in the regulation of PD-L1 expression remains unclear. The use of physiological, genetically engineered mouse models (GEMMs) of human cancer may accelerate the preclinical development of immunotherapies targeting complex cancer-host interactions and improve our understanding of the regulation of PD-L1 in cancer. Here, we discover that widely used, autochthonous GEMMs of Ras-driven lung cancer are poorly immunogenic and refractory to immunotherapies, questioning their disease-relevance and suitability for the preclinical study of immunotherapies in their current form. In addition, we investigate the molecular basis of tumour cell PD-L1 expression in lung cancer. We report that oncogenic RAS signalling is sufficient to upregulate tumour cell PD-L1 expression. Mechanistically, RAS signalling increases PD-L1 mRNA stability by modulating the AU-rich element-binding protein tristetraprolin (TTP). TTP negatively regulates PD-L1 expression through AU-rich elements in the 3’UTR of PD-L1 mRNA. In human and mouse lung cancer, TTP expression is reduced and its restoration in tumour cells enhances anti-tumour immunity. Our findings have implications for the interpretation of tumour PD-L1 expression as a biomarker for patient response to immunotherapies, and suggest a role for oncogenic RAS signalling in immune evasion.

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