The majority of cancer patients die of metastatic disease. Immunotherapy is currently one of the few successful therapeutic modalities for treating metastatic disease. Unfortunately the approved immunotherapies that target the immune checkpoints CTLA4 and PD1 have shown limited benefit for breast cancer patients.
One key to understanding why is to determine whether the immune system and immunotherapies control metastatic cancer growth at the clonal level. In particular whether certain pre-existing cancer cell clones are innately more resistant to the immune system or immunotherapy. Cellular DNA barcoding is a powerful technique that can address this question as it allows for the analysis of cancer at the clonal level. I have introduced a DNA barcode library (ClonTracer) into murine metastatic breast cancer cells (4T1) in such a way that each cell only gets a single unique barcode. I have then compared the number of unique barcodes detected at metastatic sites in wild-type mice with immune-compromised mice; in addition I have compared wild-type mice treated with combination anti-PD1/anti-CTLA4 immunotherapy with control treated mice. These studies have demonstrated that the immune system reduces the number of 4T1 clones that form metastases in the lungs and that this can be further reduced through the use of immune checkpoint inhibitors. We are now validating these findings and determining if common pre-existing clones are more resistant to the immune system and immunotherapies. We will then look to understand the key molecular pathways that differentiate resistant cell clones from susceptible clones.
This study demonstrates that the immune system can control the number of cancer cell clones that form metastases and that immunotherapies allow the immune system to control a greater number of metastatic clones. We aim to use this information to increase our understanding of how breast cancer evades the immune system and apply this knowledge to improve the success of immunotherapy regimes for metastatic breast cancer patients.