Association of cervical cancer with the presence of CD4+ regulatory T cells specific for human papillomavirus antigens.
Because of their important role in the maintenance of self-tolerance, CD4(+) regulatory T cells prevent autoimmune diseases but also curtail the efficacy of T cell immune responses against cancers. We now show that this suppressive action of CD4(+) regulatory T cells is not limited to cancers displaying tumor-associated self antigens, such as melanomas, but also extends to human papillomavirus (HPV)-positive cervical cancers that express foreign tumor antigens. HPV-specific CD4(+) T cells isolated from lymph node biopsies of cervical cancer patients were found to suppress proliferation and cytokine (IFN-gamma, IL-2) production by responder T cells. The capacity of HPV-specific CD4(+) T cells to exert this suppressive effect depended on their activation by cognate HPV antigen and on close-range interactions with responder T cells. HPV-specific CD4(+) regulatory T cells were also retrieved from cervical cancer biopsies, suggesting that they interfere with the anti-tumor immune response at both the induction and effector levels. Our findings offer a plausible explanation for the observed failure of the tumor-specific immune response in patients with cervical carcinoma.
van der Burg
Sjoerd H
SH
Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. shvdburg@lumc.nl
Piersma
Sytse J
SJ
de Jong
Annemieke
A
van der Hulst
Jeanette M
JM
Kwappenberg
Kitty M C
KM
van den Hende
Muriel
M
Welters
Marij J P
MJ
Van Rood
Jon J
JJ
Fleuren
Gert Jan
GJ
Melief
Cornelis J M
CJ
Kenter
Gemma G
GG
Offringa
Rienk
R
D052685:Alphapapillomavirus / Q000737:chemistry* / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D001706:Biopsy; D002469:Cell Separation; D002999:Clone Cells; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000166:cytology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D010641:Phenotype; D012882:Skin Tests; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology / Q000821:virology*
D000956:Antigens, Viral; D007376:Interleukin-2