Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 200, Issue 3, Pages 297-306Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20031435
Keywords
immunotherapy; antigen; cancer vaccine; epitopes; T lymphocytes
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Funding
- NCI NIH HHS [P50 CA062924, CA62924, R01CA71806] Funding Source: Medline
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Tumor-specific CD8(+) T cells can potentially be activated by two distinct mechanisms of major histocompatibility complex class I-restricted antigen presentation as follows: direct presentation by tumor cells themselves or indirect presentation by professional antigen-presenting cells (APCs). However, controversy still exists as to whether indirect presentation (the cross-priming mechanism) can contribute to effective in vivo priming of tumor-specific CD8(+) T cells that are capable of eradicating cancer in patients. A clinical trial of vaccination with granulocyte macrophage-colony stimulating factor-transduced pancreatic cancer lines was designed to test whether cross-presentation by locally recruited APCs can activate pancreatic tumor-specific CD8+ T cells. Previously, we reported postvaccination delayed-type hypersensitivity (DTH) responses to autologous tumor in 3 out of 14 treated patients. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers. We report here the consistent induction of CD8(+) T cell responses to multiple HLA-A2, A3, and A24-restricted mesothelin epitopes exclusively in the three patients with vaccine-induced DTH responses. Importantly, neither of the vaccinating pancreatic cancer cell lines expressed HLA-A2, A3, or A24. These results provide the first direct evidence that CD8(+) T cell responses can be generated via cross-presentation by an immunotherapy approach designed to recruit APCs to the vaccination site.
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