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
相关论文
共 50 条
  • [1] A shift to a peripheral Th2-type cytokine pattern during the carcinogenesis of cervical cancer becomes manifest in CINIII lesions
    Bais, AG
    Beckmann, I
    Lindemans, J
    Ewing, PC
    Meijer, CJLM
    Snijders, PJF
    Helmerhorst, TJM
    [J]. JOURNAL OF CLINICAL PATHOLOGY, 2005, 58 (10) : 1096 - 1100
  • [2] Baldwin PJ, 2003, CLIN CANCER RES, V9, P5205
  • [3] HPV infections and immunosuppression
    Bavinck, JNB
    Berkhout, RJM
    [J]. CLINICS IN DERMATOLOGY, 1997, 15 (03) : 427 - 437
  • [4] Effect of TA-CIN (HPV 16 L2E6E7) booster immunisation in vulval intraepithelial neoplasia patients previously vaccinated with TA-HPV (vaccinia virus encoding HPV 16/18 E6E7)
    Davidson, EJ
    Faulkner, RL
    Sehr, P
    Pawlita, M
    Smyth, LJC
    Burt, DJ
    Tomlinson, AE
    Hickling, J
    Kitchener, HC
    Stern, PL
    [J]. VACCINE, 2004, 22 (21-22) : 2722 - 2729
  • [5] de Gruijl TD, 1998, CANCER RES, V58, P1700
  • [6] Human papillomavirus type 16-positive cervical cancer is associated with impaired CD4+T-cell immunity against early antigens E2 and E6
    de Jong, A
    van Poelgeest, MIE
    van der Hulst, JM
    Drijfhout, JW
    Fleuren, GJ
    Melief, CJM
    Kenter, G
    Offringa, R
    van der Burg, SH
    [J]. CANCER RESEARCH, 2004, 64 (15) : 5449 - 5455
  • [7] Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 L2E7E6 fusion protein vaccine
    de Jong, A
    O'Neill, T
    Khan, AY
    Kwappenberg, KMC
    Chisholm, SE
    Whittle, NR
    Dobson, JA
    Jack, LC
    Roberts, JS
    Offringa, R
    van der Burg, SH
    Hickling, JK
    [J]. VACCINE, 2002, 20 (29-30) : 3456 - 3464
  • [8] de Jong A, 2002, CANCER RES, V62, P472
  • [9] El-Sherif AM, 2001, J PATHOL, V195, P179, DOI 10.1002/path.929
  • [10] Phase 1 study of HPV16-specific immunotherapy with E6E7 fusion protein and ISCOMATRIX™ adjuvant in women with cervical intraepithelial neoplasia
    Frazer, IH
    Quinn, M
    Nicklin, JL
    Tan, J
    Perrin, LC
    Ng, P
    O'Connor, VM
    White, O
    Wendt, N
    Martin, J
    Crowley, JM
    Edwards, SJ
    McKenzie, AW
    Mitchell, SV
    Maher, DW
    Pearse, MJ
    Basser, RL
    [J]. VACCINE, 2004, 23 (02) : 172 - 181