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*
Surgery Branch, Division of Clinical Sciences, National Cancer Institute,
Department of Transfusion Medicine, Clinical Center, and
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Selective blunting of the status of activation of circulating
tumor-specific T cells was invoked to explain their paradoxical
coexistence with unhampered tumor growth. By analogy, lack of tumor
regression in the face of observable melanoma vaccine-induced T cell
responses might be attributed to their status of activation. We
enumerated with HLA-A*0201/peptide tetramers (tHLA) vaccine-elicited T
cell precursor frequency directly in PBMC of patients with melanoma
undergoing vaccination with the HLA-A*0201-associated
gp100:209–217(210 M) epitope (g209-2 M). Furthermore, we tested by
intracellular (IC)-FACS analysis and quantitative real-time PCR
(qRT-PCR) the ability of postvaccination PBMC to produce cytokine in
response to challenge with vaccine-related epitopes or vaccine-matched
(HLA-A*0201) melanoma cells. Vaccine-induced enhancement of T cell
precursor frequency could be detected with tHLA in PBMC from six of
eight patients studied at frequencies ranging between 0.3 and 2.3% of
the total CD8+ population. Stimulation with vaccine-related
epitopes induced IFN-
expression detectable by IC-FACS or qRT-PCR,
respectively, in five and six of these patients. Furthermore,
down-regulation of tHLA staining was noted upon cognate stimulation
that could be utilized as an additional marker of T cell
responsiveness. Finally, we observed in six patients an enhancement of
reactivity against vaccine-matched tumor targets that was partly
independent of documented vaccine-specific immune responses. A strong
correlation was noted between tHLA staining of postvaccination PBMC and
IFN- expression by the same samples upon vaccine-relevant
stimulation and assessed either by IC-FACS or qRT-PCR. Thus, blunting
of the status of T cell activation on itself cannot easily explain the
lack of clinical responses observed with
vaccination.
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