Lack of ex vivo peripheral and intrahepatic α-fetoprotein-specific CD4+ responses in hepatocellular carcinoma

✍ Scribed by Mario Witkowski; Hans Christian Spangenberg; Christoph Neumann-Haefelin; Nico Büttner; Ekaterina Breous; Nadine Kersting; Oliver Drognitz; Ulrich T. Hopt; Hubert E. Blum; Nasser Semmo; Robert Thimme

• Book ID: 102863161
• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: French
• Weight: 744 KB
• Volume: 129
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.25866

✦ Synopsis

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor prognosis and limited therapeutic options that is often characterized by the expression of the tumor‐associated antigen α‐fetoprotein (AFP). CD4+ helper T cells are important in generating potent anticancer immunity as they prime and expand CD8+ T‐cell memory and may also have direct antitumor activity. However, very little information is currently available about the relative frequency, immunodominance and peripheral versus intratumoral distribution of AFP‐specific CD4+ T‐cell responses in patients with HCC. We, therefore, analyzed AFP‐specific CD4+ responses in blood and tumor tissue of patients with HCC by using overlapping peptides spanning the entire AFP protein and novel sensitive approaches such as antigen‐specific upregulation of CD154. We found that AFP‐specific CD4+ T‐cell responses were not detectable in the peripheral blood ex vivo. However, after in vitro stimulation, AFP‐specific CD4+ T‐cell responses were detectable in a large fraction of patients targeting different previously unreported epitopes with no clear immunodominance. These results indicate that AFP‐specific CD4+ T‐cell responses are not completely deleted but only present at very low frequencies. Importantly, AFP‐specific CD4+ T‐cell responses were also rarely detectable in tumor tissue, suggesting that the relative absence of these cells in the circulation ex vivo is not due to a rapid accumulation to the tumor side. Taken together, these results suggest that the lack of sufficient CD4+ T‐cell help, especially within the tumor tissue, may be one central mechanism responsible for the failure of AFP‐specific immune responses to control HCC progression.