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Glioma-associated antigen HEATR1 induces functional cytotoxic T lymphocytes in patients with glioma.

Wu ZB, Qiu C, Zhang AL, Cai L, Lin SJ, Yao Y, Tang QS, Xu M, Hua W, Chu YW, Mao Y, Zhu JH, Xu J, Zhou LF - J Immunol Res (2014)

Bottom Line: Here, we show that HEAT repeat containing 1 (HEATR1) expression in GBM tissues was significantly higher than that in control brain tissues.The peptides HEATR(1682-690), HEATR(11126-1134), and HEATR(1757-765) had high affinity for binding to HLA-A∗02:01 and a strong capacity to induce CTL response.CTLs against HEATR1 peptides were capable of recognizing and lysing GBM cells and GSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China ; Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China ; Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

ABSTRACT
A2B5+ glioblastoma (GBM) cells have glioma stem-like cell (GSC) properties that are crucial to chemotherapy resistance and GBM relapse. T-cell-based antigens derived from A2B5+ GBM cells provide important information for immunotherapy. Here, we show that HEAT repeat containing 1 (HEATR1) expression in GBM tissues was significantly higher than that in control brain tissues. Furthermore, HEATR1 expression in A2B5+ U87 cells was higher than that in A2B5-U87 cells (P = 0.016). Six peptides of HEATR1 presented by HLA-A∗02 were selected for testing of their ability to induce T-cell responses in patients with GBM. When peripheral blood mononuclear cells from healthy donors (n = 6) and patients with glioma (n = 33) were stimulated with the peptide mixture, eight patients with malignant gliomas had positive reactivity with a significantly increased number of responding T-cells. The peptides HEATR(1682-690), HEATR(11126-1134), and HEATR(1757-765) had high affinity for binding to HLA-A∗02:01 and a strong capacity to induce CTL response. CTLs against HEATR1 peptides were capable of recognizing and lysing GBM cells and GSCs. These data are the first to demonstrate that HEATR1 could induce specific CTL responses targeting both GBM cells and GSCs, implicating that HEATR1 peptide-based immunotherapy could be a novel promising strategy for treating patients with GBM.

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HLA-A02 binding affinity of six candidate peptides. (a) Flow cytometry results of HEATR1mix. (b) The binding activity of selected peptides to HLA-A∗02 molecule was determined semiquantitatively by measuring peptide-induced expression of HLA-A∗02 on T2 cells with flow cytometry. Data from three independent experiments were expressed as the mean ± SE. Unrelated 15-mer peptides were considered as control peptide.
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fig2: HLA-A02 binding affinity of six candidate peptides. (a) Flow cytometry results of HEATR1mix. (b) The binding activity of selected peptides to HLA-A∗02 molecule was determined semiquantitatively by measuring peptide-induced expression of HLA-A∗02 on T2 cells with flow cytometry. Data from three independent experiments were expressed as the mean ± SE. Unrelated 15-mer peptides were considered as control peptide.

Mentions: The T2-cell-peptide binding test was used to evaluate the binding affinity of these candidate epitope peptides for HLA-A∗02 with flow cytometry in vitro (Figure 2(a)). As shown in Figure 2(b), HEATR1682–690 had the highest affinity for HLA-A∗02:01 and the percentage of MFI increase was 308.5 ± 4.8%. The percentages of MFI increase of HEATR12102–2110, HEATR11126–1134, and HEATR1757–765 were 285.2 ± 49.2%, 287.2 ± 7.7%, and 228.7 ± 5.4%, respectively. HEATR12003–2011 was a lower affinity peptide, while HEATR11411–1419 had the lowest affinity for binding to HLA-A∗02.


Glioma-associated antigen HEATR1 induces functional cytotoxic T lymphocytes in patients with glioma.

Wu ZB, Qiu C, Zhang AL, Cai L, Lin SJ, Yao Y, Tang QS, Xu M, Hua W, Chu YW, Mao Y, Zhu JH, Xu J, Zhou LF - J Immunol Res (2014)

HLA-A02 binding affinity of six candidate peptides. (a) Flow cytometry results of HEATR1mix. (b) The binding activity of selected peptides to HLA-A∗02 molecule was determined semiquantitatively by measuring peptide-induced expression of HLA-A∗02 on T2 cells with flow cytometry. Data from three independent experiments were expressed as the mean ± SE. Unrelated 15-mer peptides were considered as control peptide.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4121097&req=5

fig2: HLA-A02 binding affinity of six candidate peptides. (a) Flow cytometry results of HEATR1mix. (b) The binding activity of selected peptides to HLA-A∗02 molecule was determined semiquantitatively by measuring peptide-induced expression of HLA-A∗02 on T2 cells with flow cytometry. Data from three independent experiments were expressed as the mean ± SE. Unrelated 15-mer peptides were considered as control peptide.
Mentions: The T2-cell-peptide binding test was used to evaluate the binding affinity of these candidate epitope peptides for HLA-A∗02 with flow cytometry in vitro (Figure 2(a)). As shown in Figure 2(b), HEATR1682–690 had the highest affinity for HLA-A∗02:01 and the percentage of MFI increase was 308.5 ± 4.8%. The percentages of MFI increase of HEATR12102–2110, HEATR11126–1134, and HEATR1757–765 were 285.2 ± 49.2%, 287.2 ± 7.7%, and 228.7 ± 5.4%, respectively. HEATR12003–2011 was a lower affinity peptide, while HEATR11411–1419 had the lowest affinity for binding to HLA-A∗02.

Bottom Line: Here, we show that HEAT repeat containing 1 (HEATR1) expression in GBM tissues was significantly higher than that in control brain tissues.The peptides HEATR(1682-690), HEATR(11126-1134), and HEATR(1757-765) had high affinity for binding to HLA-A∗02:01 and a strong capacity to induce CTL response.CTLs against HEATR1 peptides were capable of recognizing and lysing GBM cells and GSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China ; Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China ; Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

ABSTRACT
A2B5+ glioblastoma (GBM) cells have glioma stem-like cell (GSC) properties that are crucial to chemotherapy resistance and GBM relapse. T-cell-based antigens derived from A2B5+ GBM cells provide important information for immunotherapy. Here, we show that HEAT repeat containing 1 (HEATR1) expression in GBM tissues was significantly higher than that in control brain tissues. Furthermore, HEATR1 expression in A2B5+ U87 cells was higher than that in A2B5-U87 cells (P = 0.016). Six peptides of HEATR1 presented by HLA-A∗02 were selected for testing of their ability to induce T-cell responses in patients with GBM. When peripheral blood mononuclear cells from healthy donors (n = 6) and patients with glioma (n = 33) were stimulated with the peptide mixture, eight patients with malignant gliomas had positive reactivity with a significantly increased number of responding T-cells. The peptides HEATR(1682-690), HEATR(11126-1134), and HEATR(1757-765) had high affinity for binding to HLA-A∗02:01 and a strong capacity to induce CTL response. CTLs against HEATR1 peptides were capable of recognizing and lysing GBM cells and GSCs. These data are the first to demonstrate that HEATR1 could induce specific CTL responses targeting both GBM cells and GSCs, implicating that HEATR1 peptide-based immunotherapy could be a novel promising strategy for treating patients with GBM.

Show MeSH
Related in: MedlinePlus