Multidrug-resistance proteins are weak tumor associated antigens for colorectal carcinoma

Using the reverse immunology approach, 30 HLA-A2.1 restricted MDR and MRP derived peptides (MDP) were selected. Stimulated T cell lines grew well and mainly contained activated CD8+ cells. Peptide specificity and HLA-A2.1 restriction were proven in IFN-γ-ELISpot analyses and in cytotoxicity tests against MDP loaded target cells for a total of twelve peptides derived from MDR-1, MDR-3, MRP-1, MRP-2, MRP-3 and MRP-5. Of note, two of these epitopes are shared between MDR-1 and MDR-3 as well as MRP-2 and MRP-3. However, comparably weak cytotoxic activities were additionally observed against HLA-A2.1+ tumor cells even after upregulation of MDR protein expression by in vitro chemotherapy.Taken together, these data demonstrate that human T cells can be sensitised towards MDPs and hence, there is no absolute immunological tolerance. However, our data also hint towards rather low endogenous tumor cell processing and presentation of MDPs in the context of HLA-A2.1 molecules. Consequently, we conclude that MDR and MRP proteins must be considered as weak tumor specific antigens-at least for colorectal carcinoma. Their direct contribution to therapy-failure implies however, that it is worth to further pursue this approach.Chemotherapy is, apart from resection and irradiation, the most common form of cancer treatment [1]. Unfortunately, many patients' tumors acquire drug resistance, including the classical multidrug resistance (MDR), during or after this kind of therapy. Therefore, this resistance against multiple even chemically and structurally unrelated chemotherapeutic agents, after treatment with a single drug, remains a major obstacle to overcome in the field of cancer therapy [1-3]. There are many different mechanisms of acquiring resistance including mutation or overexpression of the drug's targets as well as inactivation or efflux of the drug itself [4]. In the case of drug efflux, the MDR phenomenon is accompanied by the synthesis of P-glycoprotein, a member of the ATP-