The Journal of Experimental Medicine
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Published 2 August 2004. doi:10.1084/jem.20031435
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 3, 297-306
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*Pancreatic Cancer
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Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients

Amy Morck Thomas1, Lynn M. Santarsiero1, Eric R. Lutz1,2, Todd D. Armstrong1, Yi-Cheng Chen1, Lan-Qing Huang1, Daniel A. Laheru1, Michael Goggins3, Ralph H. Hruban3, and Elizabeth M. Jaffee1,2,3

1 Department of Oncology, 2 The Graduate Program in Immunology, and 3 Department of Pathology, The Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21231

Address correspondence to Elizabeth Jaffee, Dept. of Oncology, The Sidney Kimmel Cancer Center at Johns Hopkins, The Bunting-Blaustein Cancer Research Bldg., Rm. 4M07, 1650 Orleans St., Baltimore, MD 21231. Phone: (410) 955-2957; Fax: (410) 614-8216; email: ejaffee{at}jhmi.edu

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.

Key Words: immunotherapy • antigen • cancer vaccine • epitopes • T lymphocytes

Abbreviations used in this paper: DTH, delayed-type hypersensitivity; SAGE, serial analysis of gene expression.


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