As cancers develop and spread they must continually evade immune destruction. Understanding mechanisms of immune evasion in cancer is clinically significant because of the remarkable therapeutic response of some cancer patients treated with the immune checkpoint inhibitors. Breast cancer is known to be highly immune evasive and responds poorly to the current immunotherapies, indicating a need for alternative immune pathways to be targeted. However, cell intrinsic mechanisms of immune evasion in breast cancer are largely unknown.
DNA barcoding technology offers new perspectives on immune evasion. By stably integrating each cell with a unique DNA barcode sequence, we can study clonal immune evasion in vivo. Using this technology, we previously identified cancer cell clones from the 4T1 murine mammary carcinoma cell line that are highly enriched in lung metastases following treatment with combination immunotherapy (anti-CTLA-4 plus anti-PD-1). We have now isolated these specific highly immune evasive clones and established them as clonal cell lines. These evasive clones show differences in cell morphology, proliferation and expression of classical MHC I molecules. We are currently analysing bulk RNA sequencing data to compare our highly immune evasive clones to less evasive clones and the bulk 4T1 cell line. We anticipate identifying differences in gene expression that will indicate mechanisms and pathways that enable immune evasion in these cells. Searching publicly available patient datasets will allow us to prioritise clinically relevant candidate genes and pathways for in vivo validation. We aim to identify targetable pathways that sensitise cells to immune destruction in combination with the immune check point inhibitors.
We have isolated highly immune evasive clones in the 4T1 murine model of breast cancer. By characterising these cells, we aim to identify new cell intrinsic mechanisms of immune escape in breast cancer. Targeting these newly identified mechanisms of immune evasion may improve patient response when targeted in combination with the immune checkpoint inhibitors and increase long term survival of breast cancer patients.