High frequency of functionally active Melan-A-specific T cells in a patient with progressive immunoproteasome-deficient melanoma

被引:51
作者
Meidenbauer, N
Zippelius, A
Pittet, MJ
Laumer, M
Vogl, S
Heymann, J
Rehli, M
Seliger, B
Schwarz, S
Le Gal, FA
Dietrich, PY
Andreesen, R
Romero, P
Mackensen, A
机构
[1] Univ Regensburg, Dept Hematol Oncol, D-93042 Regensburg, Germany
[2] Univ Regensburg, Dept Pathol, D-93042 Regensburg, Germany
[3] Univ Lausanne Hosp, Ludwig Inst Canc Res, Div Clin Oncoimmunol, Lausanne, Switzerland
[4] Univ Mainz, Dept Internal Med, D-6500 Mainz, Germany
[5] Univ Hosp Geneva, Lab Tumor Immunol, Div Oncol, Geneva, Switzerland
关键词
D O I
10.1158/0008-5472.CAN-04-1341
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Tumor-reactive T cells play an important role in cancer immunosurveillance. Applying the multimer technology, we report here an unexpected high frequency of Melan-A-specific CTLs in a melanoma patient with progressive lymph node metastases, consisting of 18 and 12.8% of total peripheral blood and tumor-infiltrating CD8(+) T cells, respectively. Melan-A-specific CTLs revealed a high cytolytic activity against allogeneic Melan-A-expressing target cells but failed to kill the autologous tumor cells. Loading of the tumor cells with Melan-A peptide reversed the resistance to killing, suggesting impaired function of the MHC class I antigen processing and presentation pathway. Mutations of the coding region of the HLA-A2 binding Melan-A(26)-(3), peptide or down-regulation of the MHC class I heavy chain, the antigenic peptide TAP, and tapasin could be excluded. However, PCR and immunohistochemical analysis revealed a deficiency of the immunoproteasomes low molecular weight protein 2 and low molecular weight protein 7 in the primary tumor cells, which affects the quantity and quality of generated T-cell epitopes and might explain the resistance to killing. This is supported by our data, demonstrating that the resistance to killing can be partially reversed by pre-exposure of the tumor cells to IFN-gamma, which is known to induce the immunoproteasomes. Overall, this is the first report of an extremely high frequency of tumor-specific CTLs that exhibit competent T-cell-effector functions but fail to lyse the autologous tumor cells. Immunotherapeutic approaches should not only focus on the induction of a robust antitumor immune response, but should also have to target tumor immune escape mechanisms.
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收藏
页码:6319 / 6326
页数:8
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