Cripto-1 : potential target for cancer immunotherapy?!

Abstract

Cancer immunotherapy refers to the stimulation of the immune system to eliminate cancer cells and can be applied by several different means. One form of cancer immunotherapy is therapeutic vaccination with the goal to generate de novo, and boost existing tumor antigen specific T cells. A crucial step in the development of a cancer vaccine is antigen selection. Ideally, an antigen should be uniquely expressed by tumor cells with low or no expression in healthy tissue. Also, the antigen should also be immunogenic and expressed on the cell surface, to be targetable both by cellular and humoral immunity. Cripto-1 (Cr-1) is a membrane bound oncofetal glycoprotein expressed in human cancer. Furthermore, Cr-1 is involved in epithelial-mesenchymal transition and found to be expressed by cancer stem cells (CSC). Thus, Cr-1 could represent a potential candidate for cancer immunotherapy. Circulating Cr-1 has also been found at elevated levels in patients with cancer and has been proposed as a biomarker in patients with non-small cell lung cancer. However, T cell reactivity against Cr-1 has not yet been reported in humans. We studied if vaccination against Cr-1 would result in protective anti-tumor immunity in models of melanoma and breast cancer. Furthermore, we explored the potential of soluble Cr-1 as a prognostic biomarker for patients with advanced melanoma and evaluated peripheral T cell reactivity to Cr-1 in these patients.

We found that Cr-1 DNA vaccination elicits a Cr-1 specific cellular and humoral immune response in C57Bl/6 and BALB/c mice respectively. The induced Cr-1 directed immune response was protective in murine melanoma and mammary carcinoma models. Prophylactic vaccination particularly reduced metastatic burden and partially prevented tumor formation from CSC. In patients with advanced melanoma we showed that low serum levels of soluble Cr-1 after surgery correlated with longer survival. Additionally, we detected Cr-1 reactive T cells in peripheral blood of patients with advanced melanoma and the presence of Cr-1 reactive T cells before surgery correlated with improved survival.

In summary, vaccination against Cr-1 elicits antigen-specific protective immune responses against melanoma and breast cancer. Furthermore, soluble Cr-1 protein and T cell reactivity against Cr-1 can serve as biomarkers in patients with advanced melanoma. Altogether, our observations demonstrate that Cr-1 is a potential target for cancer immunotherapy.