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HPV16 E629-38-specific T cells kill cervical carcinoma cells despite partial evasion of T-cell effector function

Thomas, K. J., Smith, K. L., Youde, Sarah Jane, Evans, Mererid, Fiander, Alison Nina, Borysiewicz, L. K. and Man, Stephen Tzekwung ORCID: 2008. HPV16 E629-38-specific T cells kill cervical carcinoma cells despite partial evasion of T-cell effector function. International Journal of Cancer 122 (12) , pp. 2791-2799. 10.1002/ijc.23475

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Persistent human papillomavirus type 16 (HPV16) infection is associated with the development of more than 50% of cervical cancers. The HPV16 E6 and E7 oncoproteins are constitutively expressed in cervical carcinomas and are attractive targets for cytotoxic T lymphocyte (CTL)-based immunotherapy. However, cervical carcinomas may possess multiple evasion mechanisms for HPV16 E6/E7-specific CTL. In this study, we investigated whether HPV16+ cervical carcinoma cell lines (CaCxCL) could evade all effector functions of HPV16 E629-38-specific T cells. Such CD8+ T cells were detected in the blood (4/10) or invaded lymph node (1/1) of cervical cancer patients using HLA-A*0201/HPV16 E629-38 tetramers after in vitro stimulation. T cells cultured from 3 different donors killed HPV16 E629-38 peptide-pulsed target cells but not HPV16+ CaCxCL in 51Cr release assays. The absence of killing correlated with limited T-cell degranulation against CaCxCL, but this was not due to antigen processing defects per se; CaCxCL could induce specific T-cell release of IFN-γ and TNF-α, and CaCxCL could be killed in longer cytotoxicity assays (>20 hr). Interestingly, the ‘slow’ killing of CaCxCL could be partially inhibited by concanamycin A, a known perforin inhibitor. The results suggest that CaCxCL was only partially activating T cells, but this was still sufficient for slow killing. Overall, our results highlight the need to examine multiple T-cell effector functions in the context of endogenous antigen presentation by tumour cells. In this study, testing for cytotoxicity using short-term assays only would have ruled out a candidate epitope for immunotherapy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Neuroscience and Mental Health Research Institute (NMHRI)
Uncontrolled Keywords: human papillomavirus; Tlymphocytes; cervical cancer
Publisher: Wiley & Sons
ISSN: 1097-0215
Last Modified: 18 Oct 2022 13:59

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