(BBSRC DTP) The role of miRNAs in cancer immunoediting

Approximately 1:3 individuals will develop some form of cancer during their lifetime. Whilst monitoring by the body’s immune system (immunosurveillance) prevents development of many would-be tumours, other malignancies evade immunosurveillance and progress to more advanced cancers. It is essential to understand the molecular mechanisms leading to the evasion of immunosurveillance by cancer cells and how these cells subsequently escape immune reactions that could eliminate them. Perturbation of the homeostasis of the endoplasmic reticulum in cancer cells contributes to this evasion. Endoplasmic reticulum proteins are important components of the transporter associated with antigen processing (TAP), a multiprotein complex that is critical for the loading of tumour antigen to the major histocompatibility complex (MHC) class I and presentation of the antigen to immune cells such as the cytotoxic T lymphocytes. Cancer cells “hide” from the immune system by preventing the construction of TAP and inhibiting the expression of MHC class I, thereby downregulating antigen presentation and inducing immunosuppression within the tumour microenvironment [1].

Cancer cells overexpress a type of short non coding RNAs, usually 22 nucleotides long, called microRNAs (miRNAs) which inhibit the formation of TAP and the MHC class I - antigen complex. Expression of these molecules is dependent on both the type of cancer and the stage of the disease therefore miRNAs are considered to be well established cancer biomarkers. The functions of miRNAs include the downregulation of gene expression of endoplasmic reticulum genes involved in the process of tumour antigen presentation and hence suppression of cancer immunorecognition. These observations led to our interest in investigating the possibility of manipulating the miRNAs, targeting specifically those that inhibit MHC class I mediated tumour antigen presentation and enhance tumourigenicity [2].

The objective of this project is to identify the miRNAs that alter the expression and the function of key endoplasmic reticulum proteins in the process of tumour antigen presentation. These include members of the Protein Disulphide Isomerases (PDIs) family important for both tumour antigen presentation and breast cancer therapy. Findings will facilitate the development of novel personalized immunotherapies.

This project involves a combination of molecular, biological and biochemical methodologies as well as biophysics, and bioinformatics approaches and would suit an applicant with a strong interest in molecular pharmacology and cancer biology. The successful candidate would develop skills in molecular pharmacology, biochemistry and proteomics, and acquire experience in biophysics and bioinformatics. Upon completion, a research career within academia or industry would be anticipated.