Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients.
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.
Department of Oncology, The Sidney Kimmel Cancer Center at Johns Hopkins, The Bunting-Blaustein Cancer Research Bldg., Rm. 4M07, 1650 Orleans St., Baltimore, MD 21231, USA.
Amy Morck
AM
Thomas
Lynn M
LM
Santarsiero
Eric R
ER
Lutz
Todd D
TD
Armstrong
Yi-Cheng
YC
Chen
Lan-Qing
LQ
Huang
Daniel A
DA
Laheru
Michael
M
Goggins
Ralph H
RH
Hruban
Elizabeth M
EM
Jaffee
D000938:Antigen-Presenting Cells / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D002460:Cell Line; D058851:GPI-Linked Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000032:analysis; D015791:HLA-A3 Antigen / Q000032:analysis / Q000502:physiology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000209:etiology; D008562:Membrane Glycoproteins / Q000276:immunology*; D000090204:Mesothelin; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000628:therapy; D014611:Vaccination
D019496:Cancer Vaccines; D058851:GPI-Linked Proteins; D015789:HLA-A2 Antigen; D015791:HLA-A3 Antigen; D008562:Membrane Glycoproteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000090204:Mesothelin