Abstract
Over-expression of the proto-oncogene c-MYC is frequently observed in a variety of tumors and is a hallmark of Burkitt´s lymphoma. The fact that many tumors are oncogene-addicted to c-MYC, renders c-MYC a powerful target for anti-tumor therapy. Using a xenogenic vaccination strategy by immunizing C57BL/6 mice with human c-MYC protein or non-homologous peptides, we show that the human c-MYC protein, despite its high homology between mouse and man, contains several immunogenic epitopes presented in the context of murine H2b haplotype. We identified an MHC class II-restricted CD4+ T-cell epitope and therein an MHC class I-restricted CD8+ T-cell epitope (SSPQGSPEPL) that, after prime/boost immunization, protected up to 25% of mice against a lethal lymphoma challenge. Lymphoma-rejecting animals contained MHC multimer-binding CD8+ cell within the peripheral blood and displayed in vivo cytolytic activity with specificity for SSPQGSPEPL. Taken together these data suggest that oncogenic c-MYC can be targeted with specific T-cells.
Highlights
Cancer driving oncogenes frequently contain mutations in their coding sequences, but in many cases remain wildtype and acquire their oncogenic property through uncontrolled expression
To investigate if differences in amino acid sequences result in immunogenic epitopes in the murine MHC H2b genetic background, we immunized C57BL/6 mice using a vaccine comprised of a fulllength c-MYC protein as immunogen and CpG ODN1826 and IFA as adjuvants
The c-MYC protein as well as the non-homologous peptides used for immunization and restimulation contained both predicted MHC class I and class II epitopes, we investigated whether the T-cell responses observed can be attributed to the CD4+ or the CD8+ compartment, or both
Summary
Cancer driving oncogenes frequently contain mutations in their coding sequences, but in many cases remain wildtype and acquire their oncogenic property through uncontrolled expression. The proto-oncogene c-MYC plays a crucial role in the pathogenesis of a large number of human tumors including Bcell lymphomas and leukemias as well as a variety of different epithelial tumors [2]. Unlike many other proto-oncogenes whose activity is dependent on mutations, truncation or gene fusion, the oncogenicity of c-MYC is in most cases the result of loss of transcriptional control leading to over-expression and accumulation of the unmutated protein itself. Mutations within the c-MYC protein, not a prerequisite for rendering c-MYC oncogenic, have been observed in a fraction of human B-cell lymphomas [3,4,5]. In a variety of human epithelial tumors and a subset of large diffuse B-cell lymphomas, the cMYC gene is over-expressed as a consequence of gene amplification which correlates with poor prognosis [7,8]. It appears that many, if not all, routes to cancer converge on cMYC
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