Incomplete tolerance to the tumour-associated antigen MDM2.

MDM2 is a tumour-associated antigen widely expressed by normal tissues and over-expressed by many tumours of different origin. We wanted to define the level of immunological tolerance against MDM2 and explore its potential in tumour immunotherapy. Two murine MDM2 epitopes, pMDM100 and pMDM441, differ in their affinity for MHC class I molecules. Previous observations made in vitro suggested that pMDM100, due to its high affinity for K(b), induces a high level of tolerance, whereas tolerance to pMDM441, which binds poorly to D(b), is incomplete. In the present article we test the immunogenicity of these two peptides in vivo. Surprisingly, mice immunized with pMDM100 generated cytotoxic T lymphocytes (CTL) that killed tumour cell lines expressing MDM2 endogenously, indicating the existence of high-avidity CTL specific for a widely expressed protein. However, the response was limited as effector CTL disappeared after continued in vitro stimulation. While immunization with the individual MDM2 peptides did not protect against tumour challenge, mice immunized with both pMDM100 and pMDM441 were partially protected. These observations suggest that targeting of multiple epitopes may be required to vaccinate against tumours expressing elevated levels of CTL-recognized self-proteins.