Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients

AM Thomas, LM Santarsiero, ER Lutz… - The Journal of …, 2004 - rupress.org
AM Thomas, LM Santarsiero, ER Lutz, TD Armstrong, YC Chen, LQ Huang, DA Laheru…
The Journal of experimental medicine, 2004rupress.org
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 …
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.
rupress.org