An unexpectedly large polyclonal repertoire of HPV-specific T cells is poised for action in patients with cervical cancer.
The diversity and extent of the local tumor-specific T-cell response in a given individual is largely unknown. We have performed an in-depth study of the local T-cell repertoire in a selected group of patients with cervical cancer, by systematic analyses of the proportion, breadth, and polarization of human papillomavirus (HPV) E6/E7-specific T cells within the total population of tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC). Isolated T cells were stimulated with sets of overlapping E6 and E7 peptides and analyzed by multiparameter flow cytometry with respect to activation, cytokine production, and T-cell receptor Vbeta usage. HPV-specific CD4+ and CD8+ T-cell responses were detected in TIL and TDLNC and their relative contribution varied between <1% and 66% of all T cells. In general, these HPV-specific responses were surprisingly broad, aimed at multiple E6 and E7 epitopes and involved multiple dominant and subdominant T-cell receptor Vbetas per single peptide-epitope. In most patients, only few IFNgamma-producing T cells were found and the amount of IFNgamma produced was low, suggesting that these are poised T cells, rendered functionally inactive within the tumor environment. Importantly, stimulation of the TIL and TDLNC with cognate antigen in the presence of commonly used Toll-like receptor ligands significantly enhanced the effector T-cell function. In conclusion, our study suggests that within a given patient with HPV-specific immunity many different tumor-specific CD4+ and CD8+ T cells are locally present and poised for action. This vast existing local T-cell population is awaiting proper stimulation and can be exploited for the immunotherapy of cancer.
Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
Peggy J
PJ
de Vos van Steenwijk
Moniek
M
Heusinkveld
Tamara H
TH
Ramwadhdoebe
Margriet J
MJ
Löwik
Jeanette M
JM
van der Hulst
Renske
R
Goedemans
Sytse J
SJ
Piersma
Gemma G
GG
Kenter
Sjoerd H
SH
van der Burg
D016207:Cytokines / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology*; D052161:Human papillomavirus 18 / Q000276:immunology*; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D009856:Oncogene Proteins, Viral / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology* / Q000821:virology*; D012097:Repressor Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology / Q000821:virology*
D016207:Cytokines; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D018984:Epitopes, T-Lymphocyte; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16