Hierarchy of α Fetoprotein (AFP)-Specific T Cell Responses in Subjects with AFP-Positive Hepatocellular Cancer

Abstract

We identified a series of immunodominant and subdominant epitopes from α fetoprotein (AFP), restricted by HLA-A*0201, which are recognized by the human T cell repertoire. The four immunodominant epitopes have been tested for immunogenicity in vivo, in HLA-A*0201+AFP+ advanced stage hepatocellular cancer (HCC) patients, and have activated and expanded AFP-specific IFN-γ-producing T cells in these patients, despite high serum levels of this self Ag. Here, we have examined the frequency, function, and avidity of the T cells specific for subdominant epitopes from AFP. We find that T cells specific for several of these epitopes are of similar or higher avidity than those specific for immunodominant epitopes. We then tested the peripheral blood of subjects ex vivo with different levels of serum AFP for the hierarchy of response to epitopes from this Ag and find that HCC patients have detectable frequencies of circulating IFN-γ-producing AFP-specific CD8+ T cells to both immunodominant and subdominant epitopes. We find the immunodominant and subdominant peptide-specific T cells to be differentially expanded with different modes of Ag presentation. Whereas spontaneous and AFP protein-stimulated responses show evidence for immunodominance, AdVhAFP-transduced dendritic cell-stimulated responses were broader and not skewed. Importantly, these data identify subdominant epitopes from AFP that can activate high-avidity T cells, and that can be detected and expanded in HCC subjects. These subdominant epitope-specific T cells can also recognize tumor cells and may be important therapeutically.

Unmasking of α-Fetoprotein-Specific CD4+ T Cell Responses in Hepatocellular Carcinoma Patients Undergoing Embolization

“…Specific CD4 ϩ T cell responses were of a low frequency as evidenced by detection after in vitro expansion but not directly ex vivo. Similarly as other groups, we have detected AFP-specific CD8 ϩ T cell responses ex vivo in HCC (15,16).…”

“…It has been suggested that the rationale behind an effective epitope-based therapeutic vaccine is to enhance both tumor-specific CD8 ϩ and CD4 ϩ T cell responses, thus controlling tumor growth (11). A number of studies have identified AFP-specific CTLs and demonstrated their presence in patients with hepatocellular carcinoma (12)(13)(14)(15)(16). CD4 ϩ helper T cells are also important in generating potent anticancer immunity, as they can prime and expand CD8 ϩ memory T cells (17) or induce tumor regression in the absence of CD8 ϩ T cells, including MHC class II-negative or MHC class II-positive tumors (18,19).…”

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

“…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 analysis using overlapping AFP peptides, we have shown that the majority of patients with HCC showed AFP-specific CD8þ T-cell responses directed against previously unreported epitopes and that these responses were primarily detectable in the tumor tissue. 5 Importantly, however, we did not find an association between the presence of CD8þ T-cell responses to AFP and the progression or prognosis of HCC, 5 suggesting a failure of the tumor-specific CD8þ T cells to control tumor growth.…”

“…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 analysis using overlapping AFP peptides, we have shown that the majority of patients with HCC showed AFP-specific CD8þ T-cell responses …”

Immunotherapy and Hepatocellular Carcinoma

“…The expression of Alpha Fetoprotein (AFP), which normally stops after birth, is found in up to 80% of HCC. AFP-specific CD8+ T-cells have been shown to produce detectable, circulating interferon-gamma in the peripheral blood of HCC patients [7]. Glypican-3 (GPC-3) is another fetal oncoprotein found in over half of HCC, but not present on normal liver tissue.…”