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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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HEATR1 was overexpressed in GBM and in A2B5+GSCs. (a) qRT-PCR was performed to analyze the differential expression between GBM tissues (n = 22) and controlled brain tissues (n = 8). (b)-(c) IHC was performed in FFPE tissue sections of 10 primary GBM tissues (left, ×400) and 10 normal brain tissues (right, ×400). GBM tissues had higher staining score of HEATR1 protein than normal brain tissues (P = 0.015). (d) qRT-PCR was performed to analyze the differential expression between A2B5+U87 cells and A2B5−U87 cells (P = 0.0016).
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fig1: HEATR1 was overexpressed in GBM and in A2B5+GSCs. (a) qRT-PCR was performed to analyze the differential expression between GBM tissues (n = 22) and controlled brain tissues (n = 8). (b)-(c) IHC was performed in FFPE tissue sections of 10 primary GBM tissues (left, ×400) and 10 normal brain tissues (right, ×400). GBM tissues had higher staining score of HEATR1 protein than normal brain tissues (P = 0.015). (d) qRT-PCR was performed to analyze the differential expression between A2B5+U87 cells and A2B5−U87 cells (P = 0.0016).

Mentions: First, we investigated whether HEATR1 was overexpressed in GBM cells. We investigated the expression profile of HEATR1 mRNA in 22 primary GBM tissues and eight control brain tissues using quantitative RT-PCR. As shown in Figure 1(a), the expression of HEATR1 mRNA in GBM tissues was higher than that in control brain tissues (P < 0.01). In addition, IHC was initially performed in FFPE tissue sections of primary GBM (n = 10) and normal brain tissues (n = 10). As shown in Figure 1(b), HEATR1 protein was mainly localized in the tumor cell cytoplasm and nuclei. The average IHC score of HEATR1 expression in GBM and normal brain tissues was 4.4 ± 0.7 and 2.1 ± 0.4, respectively. GBM tissues had higher expressions of HEATR1 protein than normal brain tissues (Figure 1(c), P = 0.015). However, the expression level of HEATR1 proteins did not appear to be correlated with glioma grade (data not shown).


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)

HEATR1 was overexpressed in GBM and in A2B5+GSCs. (a) qRT-PCR was performed to analyze the differential expression between GBM tissues (n = 22) and controlled brain tissues (n = 8). (b)-(c) IHC was performed in FFPE tissue sections of 10 primary GBM tissues (left, ×400) and 10 normal brain tissues (right, ×400). GBM tissues had higher staining score of HEATR1 protein than normal brain tissues (P = 0.015). (d) qRT-PCR was performed to analyze the differential expression between A2B5+U87 cells and A2B5−U87 cells (P = 0.0016).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: HEATR1 was overexpressed in GBM and in A2B5+GSCs. (a) qRT-PCR was performed to analyze the differential expression between GBM tissues (n = 22) and controlled brain tissues (n = 8). (b)-(c) IHC was performed in FFPE tissue sections of 10 primary GBM tissues (left, ×400) and 10 normal brain tissues (right, ×400). GBM tissues had higher staining score of HEATR1 protein than normal brain tissues (P = 0.015). (d) qRT-PCR was performed to analyze the differential expression between A2B5+U87 cells and A2B5−U87 cells (P = 0.0016).
Mentions: First, we investigated whether HEATR1 was overexpressed in GBM cells. We investigated the expression profile of HEATR1 mRNA in 22 primary GBM tissues and eight control brain tissues using quantitative RT-PCR. As shown in Figure 1(a), the expression of HEATR1 mRNA in GBM tissues was higher than that in control brain tissues (P < 0.01). In addition, IHC was initially performed in FFPE tissue sections of primary GBM (n = 10) and normal brain tissues (n = 10). As shown in Figure 1(b), HEATR1 protein was mainly localized in the tumor cell cytoplasm and nuclei. The average IHC score of HEATR1 expression in GBM and normal brain tissues was 4.4 ± 0.7 and 2.1 ± 0.4, respectively. GBM tissues had higher expressions of HEATR1 protein than normal brain tissues (Figure 1(c), P = 0.015). However, the expression level of HEATR1 proteins did not appear to be correlated with glioma grade (data not shown).

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