Surgery followed by Persistence of High-Grade Squamous Intraepithelial Lesions Is Associated with the Induction of a Dysfunctional HPV16-Specific T-Cell Response

被引:32
作者
van Steenwijk, Peggy J. de Vos [2 ]
Piersma, Sytse J. [1 ]
Welters, Marij J. P. [3 ]
van der Hulst, Jeanette M. [1 ]
Fleuren, Gertjan [4 ]
Hellebrekers, Bart W. J. [5 ]
Kenter, Gemma G. [2 ]
van der Burg, Sjoerd H. [1 ]
机构
[1] Leiden Univ, Med Ctr, Dept Clin Oncol, NL-2300 RC Leiden, Netherlands
[2] Leiden Univ, Med Ctr, Dept Gynaecol, NL-2300 RC Leiden, Netherlands
[3] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands
[4] Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RC Leiden, Netherlands
[5] Haga Teaching Hosp, Dept Obstet & Gynaecol, The Hague, Netherlands
关键词
D O I
10.1158/1078-0432.CCR-08-0994
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: To characterize HPV16 E6- and E7-specific T-cell immunity inpatients with high-grade squamous intraepithelial lesions (HSIL). Experimental Design: Peripheral blood mononuclear cells isolated from 38 patients with HPV16+ HSIL were used to determine the magnitude, breadth, and polarization of HPV16-specific T-cell responses by proliferation assays and cytokine assays. Furthermore, HSIL-infiltrating T cells isolated from 7 cases were analyzed for the presence of HPV16 E6- and/or E7-specific T cells, phenotyped, and tested for the specific production of IFN-gamma and interleukin-10 aswell as for their capacity to suppress immune responses. Results: HPV16-specific T-cell responses were absent in the circulation of the majority (similar to 60%) of patients who visit the clinic for treatment of a HPV16+ HSIL lesion. Notably, HPV16-specific T-cell reactivity was predominantly detected in patients returning to the clinic for repetitive treatment of a persistent or recurrent HPV16+ HSIL lesion after initial destructive treatment. The majority (> 70%) of these HPV16-specific T-cell responses did not secrete proinflammatory cytokines, indicating that most of the subjects, although in principle able to mount a HPV16-specific immune response, fail to develop protective cellular immunity. This notion is sustained by our observation that only three HSIL-infiltrating T-cell cultures contained HPV16-specific Tcells, one of which clearly consisted of HPV16 E7-specific regulatory T cells. Conclusions: The presence of HPV16-specificTcells with a non-Th1/Th2 cytokine and even suppressive signature in patients with HSIL may affect the outcome of vaccine approaches aiming at reinforcing human papillomavirus-specific immunity to attack human papillomavirus-induced lesions.
引用
收藏
页码:7188 / 7195
页数:8
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