An unexpectedly large polyclonal repertoire of HPV-Specific T cells is poised for action in patients with cervical cancer

Peggy J. De Vos Van Steenwijk, Moniek Heusinkveld, Tamara H. Ramwadhdoebe, Margriet J. Löwik, Jeanette M. Van Der Hulst, Renske Goedemans, Sytse J. Piersma, Gemma G. Kenter, Sjoerd H. Van Der Burg

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53 Scopus citations

Abstract

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 Vβ 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 Vβs per single peptide-epitope. In most patients, only few IFN"y-producing T cells were found and the amount of IFNγ 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.

Original languageEnglish
Pages (from-to)2707-2717
Number of pages11
JournalCancer research
Volume70
Issue number7
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

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  • Cite this

    De Vos Van Steenwijk, P. J., Heusinkveld, M., Ramwadhdoebe, T. H., Löwik, M. J., Van Der Hulst, J. M., Goedemans, R., Piersma, S. J., Kenter, G. G., & Van Der Burg, S. H. (2010). An unexpectedly large polyclonal repertoire of HPV-Specific T cells is poised for action in patients with cervical cancer. Cancer research, 70(7), 2707-2717. https://doi.org/10.1158/0008-5472.CAN-09-4299