α-Fetoprotein Impairs APC Function and Induces Their Apoptosis

Um, Soon Ho; Mulhall, Catherine; Alisa, A; Ives, Annette; Karani, John; Williams, Roger; Bertoletti, Antonio; Behboudi, Shahriar

doi:10.4049/jimmunol.173.3.1772

Cited by 104 publications

(98 citation statements)

References 27 publications

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“…[10][11][12] Indeed, high serum AFP levels >2,500 ng/mL have been shown to impair APC function. 34 However, in our study, patients with a serum level up to >5,000 ng/mL showed AFP-specific responses; thus, no evidence of a marked immune-suppressive effect of serum AFP up to this level could be observed although only a few patients with high serum levels were enrolled in our study. It is also possible that AFP-specific CD4þ T cells undergo deletion during thymic migration, as AFP is a tumor-associated, but not completely tumor-specific antigen.…”

Section: Tumor Immunologycontrasting

confidence: 39%

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

Witkowski

Spangenberg

Büttner

et al. 2011

Intl Journal of Cancer

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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...

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Section: Tumor Immunologycontrasting

confidence: 39%

“…Possible mechanisms include an AFP-induced impairment of APCs, 34 dysfunctional dendritic cells, 35 the induction of AFPspecific TGF-b-producing CD4þ T cells 36 or the action of CD4þ CD25þ regulatory T cells. [10][11][12] Indeed, high serum AFP levels >2,500 ng/mL have been shown to impair APC function.…”

Section: Tumor Immunologymentioning

confidence: 99%

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

Witkowski

Spangenberg

Büttner

et al. 2011

Intl Journal of Cancer

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“…␣-Fetoprotein (AFP) is an oncofetal Ag with immunoregulatory properties (8) that is re-expressed in the majority of patients with HCC and used in clinical practice as a diagnostic and prognostic serum marker (9). It also serves as a tumor rejection Ag (10) and is therefore an attractive target for immunotherapy.…”

Section: Unmasking Of ␣-Fetoprotein-specific Cd4 ؉ T Cell Responses Imentioning

confidence: 99%

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

Ayaru

Pereira

Alisa

et al. 2007

The Journal of Immunology

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156

107

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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-α-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-γ and TNF-α) 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.

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“…One of the biological properties of AFP is its regulatory effects on immune response (6 -9). We have shown that APCs of hepatocellular carcinoma patients with high levels of AFP, not those with normal or mildly elevated AFP levels, are dysfunctional and in vitro AFP impairs dendritic cell function and induce their apoptosis (6). Naturally occurring immune response against AFP can be mounted in patients with hepatocellular carcinoma (10 -12), but there is limited information about its association with hepatocellular carcinoma staging and serum AFP levels.…”

mentioning

confidence: 99%

Analysis of CD4+ T-Cell Responses to a Novel α-Fetoprotein-Derived Epitope in Hepatocellular Carcinoma Patients

Alisa

Ives

Pathan

et al. 2005

Clinical Cancer Research

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Purpose: a-Fetoprotein (AFP) is a tumor-associated antigen in hepatocellular carcinoma and is a target for the development of cancer vaccine. Four immunodominant AFP-derived HLA-A*0201-restricted peptides have been identified and the administration of these peptides with an adjuvant has stimulated AFP-specific CTL responses in hepatocellular carcinoma patients. However, no AFP-derived CD4 T-cell epitope has yet been reported and the status of AFP-specific CD4 + T-cell responses in hepatocellular carcinoma patients is not fully understood. The aim of this study was to analyze naturally occurring CD4 + T-cell responses to AFP. Experimental Design: We analyzed the ability of CD4 + T cells to recognize an HLA-DR-restricted AFP-derived epitope in 41 hepatocellular carcinoma patients and 24 nonhepatocellular carcinoma control patients using intracellular cytokine assays for IFN-g. Results: Here, for the first time, we report the identification of an AFP-derived CD4 + T-cell epitope that is recognized by circulating lymphocytes from hepatocellular carcinoma patients in association with HLA-DR. The absence of detectable responses in healthy donors and patients with chronic liver disease suggests that AFP-specific CD4 + T cells in the responder patients had been previously expanded in vivo in response to the tumor. The anti-AFP CD4 + T-cell response was only detected in hepatocellular carcinoma patients with normal or mildly elevated serum AFP levels who were in the early stage of disease. Conclusion: Our data will be instrumental in the development of cancer vaccine using AFP-derived immunogens.

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α-Fetoprotein Impairs APC Function and Induces Their Apoptosis

Cited by 104 publications

References 27 publications

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

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

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

Analysis of CD4+ T-Cell Responses to a Novel α-Fetoprotein-Derived Epitope in Hepatocellular Carcinoma Patients

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