The majority of cancer patients die of metastatic disease. Immunotherapy is currently one of the few successful therapeutic modalities for treating metastatic disease. However, despite the success in metastatic melanoma patients and a few other cancer types immunotherapies have had much more limited effects in breast cancer patients. Understanding how metastatic breast cancer evades the immune system and immunotherapies will help elucidate why the current immunotherapies do not work and allow us to develop improved immunotherapy regimes.
Key to understanding this is to determine whether resistance mechanisms are clonal in origin and whether they arise due to pre-existing resistant clones or through de novo resistance mechanisms. Cellular DNA barcoding is a technique that allows for the analysis of the response of cancer cells to therapy at the clonal level. I have introduced a DNA barcode library into a metastatic breast cancer cell line (4T1) and determined that this does not impact the ability of these cells to grow and metastasise in vivo. To determine how the immune system controls metastatic outgrowth at the clonal level I have compared the barcode frequency at metastatic sites in wild-type mice with immune-compromised mice. Future studies of clonal outgrowth following treatment with the current gold-standard immunotherapy of anti-CTLA4 plus anti-PD1 will be examined. Cancer cell clones (based on DNA barcodes) that escape therapy will then be characterised at the molecular level and compared to susceptible clones.
These studies will increase our understanding of how metastatic breast cancer cells avoid the immune system and will help determine more optimal combinations of immunotherapies to effectively treat metastatic breast cancer.