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

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 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...

Prognostic significance of preoperative aspartate aminotransferase to neutrophil ratio index in patients with hepatocellular carcinoma after hepatic resection

“…CD4 + T lymphocyte cells act as a sensor in detecting precancerous cells and then regulate their eradication [32], these can prevent the occurrence and development of HCC. The loss of CD4 + T lymphocyte accompanied with the impaired activation of CD8 + T lymphocyte cells may cause the insufficient secretion of cytotoxin performing anti-carcinogenic function in the neoplastic microenvironments [33], what's more, Neutrophils potentiate cancer cell migration, invasion, and dissemination by secreting immunoreactive molecules such as hepatocyte growth factor (HGF) [34, 35], oncostatin M [36], b2-integrins [37] or neutrophil elastase [38]. With the progression of tumor diseases, the hepatic parenchymal cells are damaged, intracellular AST will be released into the blood which will cause a high concentration of serum AST.…”

Immunobiology of hepatocellular carcinoma

“…A recent study in our group found that there is a pronounced lack of helper T cells specific for AFP in blood, liver, and tumors of HCC patients especially when compared to CD8 + T cell responses against the same antigen [70,71]. Another recent study proposed that AFP specific CD4 + and CD8 + T cells expanded at different stages of disease [72].…”

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

“…A low frequency of AFP-specific CD4 + T cells has been detected in the blood circulation and in tumor tissues from early-stage HCC patients [28]. However, in advanced HCC, blood AFP levels often increase and CD4 + T cells become exhausted and loose their immune supportive function [29].…”