Abstract
Uterine serous papillary carcinoma is a highly aggressive variant of endometrial cancer histologically similar to high grade ovarian cancer. Unlike ovarian cancer, however, it is a chemoresistant disease from onset, with responses to combined cisplatinum-based chemotherapy in the order of 20% and an extremely poor prognosis. In this study, we demonstrate that tumour lysate-pulsed autologous dendritic cells can elicit a specific CD8+ cytotoxic T lymphocyte response against autologous tumour target cells in three patients with uterine serous papillary cancer. CTL from patients 1 and 2 expressed strong cytolytic activity against autologous tumour cells, did not lyse autologous lymphoblasts or autologous EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Patient 3 CD8+ T cells expressed a modest but reproducible cytotoxicity against autologous tumour cells only at the time of the first priming. Further priming attempts with PBL collected from patient 3 after tumour progression in the lumboaortic lymph nodes were unsuccesful. Cytotoxicity against autologous tumour cells could be significantly inhibited by anti-HLA class I (W6/32) and anti-LFA-1 MAbs. Highly cytotoxic CD8+ T cells from patients 1 and 2 showed a heterogeneous CD56 expression while CD56 was not expressed by non-cytotoxic CD8+ T cells from patient 3. Using two colour flow cytometric analysis of intracellular cytokine expression at the single cell level, a striking dominance of IFN-γ expressors was detectable in CTL populations of patients 1 and 2 while in patient 3 a dominant population of CD8+ T cells expressing IL-4 and IL-10 was consistently detected. Taken together, these data demonstrate that tumour lysate-pulsed DC can be an effective tool in inducing uterine serous papillary cancer-specific CD8+ CTL able to kill autologous tumour cells in vitro. However, high levels of tumour specific tolerance in some patients may impose a significant barrier to therapeutic vaccination. These results may have important implications for the treatment in the adjuvant setting of uterine serous papillary cancer patients with active or adoptive immunotherapy.British Journal of Cancer (2002) 86, 151–157. DOI: 10.1038/sj/bjc/6600026 www.bjcancer.com© 2002 The Cancer Research Campaign
Highlights
Induction of Uterine serous papillary carcinoma (USPC)-specific CD8+ CTL AD Santin et al1996), cell sonicates (Nair et al, 1997b), or messenger RNA resultant cell suspension was washed twice in RPMI 1640
The percentage of tumour cells used for tumour the immune system and provide a rationale for using DC as natur- lysate applied to the DC or used as target cells in cytotoxicity al adjuvants for human immunotherapy
In an attempt to overcome these major limitations, several investigators have recently reported induction of effective tumour immunity using DCs pulsed with unfractionated tumour-derived materials, acid eluted peptides or messenger RNA (Boczkowski et al, 1996; Nair et al, 1997a,b; Zitvogel et al, 1996)
Summary
Induction of USPC-specific CD8+ CTL AD Santin et al1996), cell sonicates (Nair et al, 1997b), or messenger RNA resultant cell suspension was washed twice in RPMI 1640. We have used autologous DCs. HLA phenotypic analysis of CD8+ cultures HLA class I typing of purified CD8+ cultures was performed by pulsed with USPC lysate to induce a tumour-specific T cell standard lymphocytotoxicity tests (Hopkins, 1990) in the tissue response from three USPC patients. Using two colour flow cytometric analysis of intracellular cytokine expression at the single cell level, we show that a strongly polarized Type 1 pattern of cytokine expression was inducible in the tumour antigen-primed CD8+ T cells of two patients, and that
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