Antigen-Specific T Cells in Breast Cancer
An independent publication from a cancer research group at Indiana University cites using Cellero antigen-specific T cell products to examine mechanisms of immune evasion.
Immune surveillance is the human body’s strongest defense against invasive cancer cells. The uncanny ability to evade that surveillance and grow aggressively is exactly what makes some types of cancer so dangerous. Breast cancer is particularly notorious for the devastating “immune silence” that often allows it to escape detection. In a paper recently published in the Journal of Clinical Investigation, the research group discussed the specific mechanisms of immune evasion that make breast cancer so difficult to treat. They focused their research on a MAL2, a protein known to be associated with aggressive, treatment-resistant breast cancer.
Cancer immunotherapy relies on boosting cytotoxic T cell responses to cancer. However, some cancer cells have been shown to downregulate cell surface antigen presentation, leaving nothing for T cells (or NK cells) to recognize so they can launch a cytotoxic immune response. The researchers hypothesized that to downregulate antigen presentation, cancer cells must possess some mechanism whereby the normal antigen presentation pathway is disrupted. Since antigens are presented at the cell surface by the MHC-1 protein complex, the researchers focused on the recycling and degradation of that complex inside the cell.
To carry out their investigations, the team used Anti-MAGE A10 and Anti-NY-ESO-1 antigen-specific T cells sourced from Cellero. Antigen-specific T cells have limited toxicity against normal cells, and are used to track anti-tumor cytotoxicity. Cytotoxicity levels indicate the degree to which antigen presentation mechanisms are impacted.
Anti-MAGE A10 T cells recognize the tumor cell surface peptide known as MAGE A10 and display cytotoxic activity against a variety of cancer cell types, including non-small cell lung cancer, testicular cancer, and melanoma. Anti-NY-ESO-1 T cells recognize NY-ESO-1 and display cytotoxic activity against a variety of cancer cell types which express that antigen on their surface. Both T cell constructs have been used in numerous cancer immunotherapy clinical trials.
For in vitro work, the activity levels of the antigen-specific T cells were evaluated against a HER2+ human breast cancer cell line known to be highly resistant to cytotoxic T cell infiltration. Primary cells derived from human breast cancer patient biopsies were used for the in vivo studies in a mouse model.
Study results showed that while the MAL2 protein was not directly involved in cancer cell proliferation, higher expression of the protein correlated strongly with a poor outcome in cancer patients. MAL2 expression also correlated with low cytotoxicity of CD8 T cells. Conversely, low expression of MAL2 correlated with higher CD8 T cell infiltration and higher cytotoxicity rates.
For the final portion of their study, the authors used a lentiviral vector delivery system to compare cancer cell lines expressing either high or low levels of MAL2. The results showed that MAL2 expression directly impacts the cytotoxicity of tumor-infiltrating CD8 T cells by increasing the turnover rate of MHC-1 complex and thus significantly decreasing the overall level of antigen presentation.
These results are remarkable. Cytotoxic T cells play a central role in many cancer immunotherapies, so understanding how some types of cancer can evade immune detection will go a long way toward increasing the effectiveness of these therapies. The authors plan to continue their studies, which they hope will result in a new, more effective strategy in the fight against cancer.
- Fang Y., et al. MAL2 drives immune evasion in breast cancer by suppressing tumor antigen presentation. Journal of Clinical Investigation. 131(1): e140837. Jan 2021.