Abstract
CD4+ helper T cells play a critical role in orchestrating host immune responses, including antitumor immunity. The limited availability of MHC class II-associated tumor antigens is still viewed as a major obstacle in the use of CD4+ T cells in cancer vaccines. Here, we describe a novel approach for the identification of MHC class II tumor-associated antigens (TAAs). By combining two-dimensional liquid chromatography and nanoelectrospray ionization tandem mass spectrometry, we developed a highly sensitive method for the detection of human leukocyte antigen (HLA)-DR-associated peptides of dendritic cells upon exposure to necrotic tumor cells. This approach led to the identification of a novel MHC class II-restricted TAA epitope derived from melanotransferrin. The epitope stimulated T cells derived from melanoma patients and healthy individuals and displayed promiscuity in HLA-DR restriction. Moreover, the same peptide was also presented by MHC class II-positive melanoma cells. This strategy may contribute to increase the number of tumor epitopes presented by MHC class II molecules and may support the development of more efficacious vaccines against cancer.
Highlights
T cells play a crucial role in the induction and maintenance of antitumor immunity
To mimic in vitro tumor cell uptake, processing and tumor antigen presentation by dendritic cells and to exploit this scenario for the identification of MHC class II–restricted tumor antigens, we established a strategy, denoted as MHC class II–associated peptide proteomics (MAPPs), www.aacrjournals.org which allows the identification of self and foreign human leukocyte antigen (HLA)-restricted peptides on as little as 1 to 5 Â 106 dendritic cells
The very same peptide could be detected in an independent experiment in which dendritic cells of a different donor of the haplotype DRB1*0101/04011 were pulsed with necrotic Ma-Mel-18a cells, suggesting that the epitope is HLA-DR4 restricted and very abundant on MHC class II molecules of dendritic cells after uptake of necrotic Ma-Mel-18a melanoma cells
Summary
T cells play a crucial role in the induction and maintenance of antitumor immunity. This could be shown in animal models and human cancer therapy (1–3). The activation of antitumor T-cell immunity relies on the recognition of tumor-associated antigens (TAAs) that bear immunogenic T-cell epitopes expressed on tumor cells. The identification of the first T-cell epitope of the tumor antigen MAGE (4) paved the way for the development of cancer vaccines, which trigger cellular immune responses executed by tumor-specific T cells. Human clinical trials applying defined MHC class I–restricted tumor antigenic peptides indicated that T-cell responses are readily detectable in vaccinated tumor patients (5, 6). The overall immune responses were often weak and transient (10, 11), and a clear association between immunologic and clinical responses has rarely been observed
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