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 a-fetoprotein (AFP). CD41 helper T cells are important in generating potent anticancer immunity as they prime and expand CD81 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 CD41 T-cell responses in patients with HCC. We, therefore, analyzed AFP-specific CD41 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 CD41 T-cell responses were not detectable in the peripheral blood ex vivo. However, after in vitro stimulation, AFP-specific CD41 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 CD41 T-cell responses are not completely deleted but only present at very low frequencies. Importantly, AFP-specific CD41 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 CD41 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.Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with a poor prognosis and limited therapeutic options. Therefore, the development of novel therapeutic strategies is of high priority. Immunotherapy represents a promising potential option for several reasons: First, a correlation has been reported between high numbers of tumor-infiltrating T cells in HCC tissue and the prognosis of disease.1,2 Second, adoptive immunotherapy with anti-CD3-and interleukin-2-stimulated autologous lymphocytes lowers postsurgical HCC recurrence rates in humans.3 Finally, the induction of anti-a-fetoprotein (AFP) cell-mediated immune responses can control tumor growth in the mouse model. 4AFP is a serum marker for HCC that is elevated in 50-80% of patients with HCC. Physiologically, AFP is highly expressed in fetal liver, gastrointestinal tract and yolk sac but is transcriptionally downregulated after birth. Importantly, after birth, AFP can be elevated in patients with HCC or testicular cancers.5 Of note, this can be associated with the emergence of AFP-specific immune responses. For example, several human leukocyte antigen (HLA) class I-restricted AFP-specific epitopes have been identified by different approaches and shown to be present in HCC patients. [6][7][8][9] Indeed, in a recent comprehensive anal...

Immunotherapy is considered a new treatment option for many tumor entities, as decades of research into cancer immunotherapy have recently yielded promising results. Indeed, impressive clinical results of checkpoint blockade inhibitors in malignant melanoma and non-small cell lung cancer indicate the therapeutic potential of tumor-specific immune restoration. Over the years, different immunotherapeutic approaches have been evaluated for the treatment of hepatocellular carcinoma (HCC) with some respectable results. In this review article, we will summarize the key studies of the past 30 years and will elucidate in which direction the dynamic field of HCC immunotherapy is currently moving.

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ZusammenfassungEine Beteiligung des Ösophagus bei der Hauterkrankung Lichen planus wurde erstmals 1982 beschrieben und fast 30 Jahre lang als eine Rarität angesehen. Untersuchungen der letzten 10 Jahre aber zeigen, dass diese Erkrankung weniger selten ist als angenommen. Es ist sogar anzunehmen, dass der ösophageale Lichen planus (Esophageal Lichen planus, ELP) häufiger ist als die Eosinophile Ösophagitis (EoE). Die Ösophagusbeteiligung betrifft meist Frauen im mittleren Alter. Das Hauptsymptom ist eine Dysphagie. Endoskopisch erkennt man in der Speiseröhre eine charakteristische Schleimhautablösung, eine Trachealisierung, und gelegentlich Hyperkeratosen und bei langem Bestehen auch Stenosen. Wegweisend ist die Histologie mit einer subepithelialen Ablösung sowie einem bandförmigen Infiltrat aus T-Lymphozyten, dem Nachweis von apoptotischen Keratinozyten (Civatte Bodies) und Dyskeratosen. Die direkte Immunfluoreszenz zeigt Fibrinogen-Ablagerungen entlang der Basalmembran. Eine etablierte Therapie gibt es bisher nicht. Die Behandlung mit topischen Steroiden ist in 2/3 der Fälle wirksam. Eine Therapie wie beim klassischen Lichen planus scheint unwirksam zu sein. Bei symptomatischen Stenosen kann eine Dilatation indiziert sein. Der ELP reiht sich in die Gruppe der „neuen“ immunologisch vermittelten Erkrankungen des Ösophagus ein.