Inflammation-induced tumor antigen expression on epithelial cells reveals the mechanism of their generation and provides a system for identification of new tumor targets

Abstract

Tumor-associated antigens (TAAs) are self-molecules abnormally expressed on tumor cells that elicit humoral and cellular immunity and are targets of effective cancer immunosurveillance. Surprisingly, immunity to TAAs is found in many healthy individuals with no history of cancer. We previously showed that other events in addition to cancer, such as viral and bacterial infections, can cause the expression of some TAAs and correlate with effective tumor immunosurveillance. We are now testing in mice the ability of two LCMV strains, one that causes acute (Armstrong) and one that causes chronic (Cl-13) infection, to elicit expression of and immune memory to TAAs and protect from a later tumor challenge. We observed that infection with the acute strain elicits immunity to specific TAAs expressed by two tumor cell lines that were then used in tumor challenge experiments. So far, we were able to show a protective effect of a previous Armstrong infection against our model of lymphoid tumor (EL4). We also developed a highly reproducible in vitro model of acute inflammation of primary epithelial cells and confirmed that short-term exposure to pro-inflammatory cytokines IL-1β, IL-6 and TNF-α leads to abnormal expression of three well known TAAs, MUC1, CEA and HER2/neu. These cells were found to activate macrophages, which should promote antigen uptake and presentation of these and other TAAs. We have used this system and 2D Difference Gel Electrophoresis (2D-DIGE) combined with mass spectrometry to identified so far seven new TAAs. Because these TAAs are generated first as disease-associated antigens (DAAs), they represent highly predictable shared antigens for safe and effective preventative cancer vaccines.