Anti-colorectal cancer immunity : control ‘the force’!

Abstract

This dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. In the first part, expression of HLA class I and expression of CXCL5 in colocectal cancer was studied. Low expression of HLA class I in rectal tumors was associated with poor survival of rectal cancer patients. Low expression of CXCL5 in cancer cells was significantly associated with poor prognosis in a population of colorectal cancer patients and correlated with presence of intra-tumoral CD8+ T-cell infiltration. In the second part of this thesis we focused on induction of tumor specific T-cells. For immunotherapeutic purposes distinction should be made between microsatellite instable (MSI-H) and microsatellite stable (MSS) colorectal tumors, as MSI-H tumors express neo-antigens __foreign__ to the immune system while immunotherapy against MSS tumors depends on tumor associated __self__-antigens. We developed a methodology predicting immunogenic behavior of frameshift-mutated antigens present in MSI-H tumors that was based on accumulation and MHC class I presentation. This method can be used to develop cancer immunotherapy of patients at risk for MSI-H tumors. In the last two chapters we described safety and immunogenicity of a p53 synthetic long peptides vaccine combined with and without Interferon-alpha. Addition of IFN-_ to the p53-SLP_ vaccine significantly improved p53-specific after vaccination. Altogether this dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. This knowledge can be used to further optimize immunotherapeutic strategies to treat cancer patients.