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-Fetoprotein-Specific CD4+ T Cell Responses in Hepatocellular Carcinoma Patients Undergoing Embolization1
* Department of Medicine, University College London Institute of Hepatology,
Academic Department of Oncology, and
University Department of Surgery and Liver Transplantation, Royal Free and University College London Medical School, University College London, London, United Kingdom;
Liver Transplantation and Hepatobiliary Medicine Unit, Royal Free Hospital, London, United Kingdom;
¶ Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
Necrosis of tumor cells can activate both innate and adaptive antitumor immunity. However, there is little information on the effects of necrosis-inducing cancer treatments on tumor-specific T cell immune responses in humans. We studied the effects of a necrosis-inducing treatment (embolization) on anti-
-fetoprotein (AFP)-specific CD4+ T cell responses in hepatocellular carcinoma (HCC) patients and controls using an array of AFP-derived peptides. In this study, we show that AFP-specific CD4+ T cell responses to three immunodominant epitopes in HCC patients were significantly expanded during (p < 0.0001) and after embolization (p < 0.002). The development of higher frequencies of AFP-specific CD4+ T cells after treatment were significantly associated with the induction of >50% necrosis of tumor and an improved clinical outcome (p < 0.007). In addition, we identified two novel HLA-DR-restricted AFP-derived CD4+ T cell epitopes (AFP137–145 and AFP249–258) and showed that the CD4+ T cells recognizing these epitopes produce Th1 (IFN-
and TNF-) but not Th2 (IL-5)-type cytokines. AFP137–145-, AFP249–258-, and AFP364–373-specific CD4+ T cells were detected in HCC patients but not in patients with chronic liver diseases or healthy donors. In conclusion; our study shows that induction of tumor necrosis by a conventional cancer treatment can unmask tumor rejection Ag cell-mediated immunity and provides a rationale for combining embolization with immunotherapy in HCC patients.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from the Pathological Society of Great Britain and Ireland (to L.A.). The support of the de Laszlo Foundation to the work of S.B. is gratefully acknowledged.
2 Address correspondence and reprint requests to Dr. Shahriar Behboudi, University College London Institute of Hepatology, Royal Free and University College London Medical School, 69-75 Chenies Mews, London WC1E 6HX, U.K. E-mail address: s.behboudi{at}ucl.ac.uk
3 Abbreviations used in this paper: TACE, transarterial chemoembolization; AFP, -fetoprotein; CT, computerized tomography; HCC, hepatocellular carcinoma; PPD, purified protein derivative; TAE, transarterial embolization.
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  A. Alisa, S. Boswell, A. A. Pathan, L. Ayaru, R. Williams, and S. Behboudi Human CD4+ T Cells Recognize an Epitope within {alpha}-Fetoprotein Sequence and Develop into TGF-{beta}-Producing CD4+ T Cells J. Immunol., April 1, 2008; 180(7): 5109 - 5117. [Abstract] [Full Text] [PDF]
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