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HPV16 E6 29‐38 ‐specific T cells kill cervical carcinoma cells despite partial evasion of T‐cell effector function
Author(s) -
Thomas Karen J.,
Smith Kelly L.,
Youde Sarah J.,
Evans Mererid,
Fiander Alison N.,
Borysiewicz Leszek K.,
Man Stephen
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23475
Subject(s) - cytotoxic t cell , ctl* , biology , degranulation , cd8 , perforin , antigen , immunology , t cell , cancer research , cytotoxicity , microbiology and biotechnology , in vitro , immune system , biochemistry , receptor
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 E6 29‐38 ‐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 E6 29‐38 tetramers after in vitro stimulation. T cells cultured from 3 different donors killed HPV16 E6 29‐38 peptide‐pulsed target cells but not HPV16 + CaCxCL in 51 Cr 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. © 2008 Wiley‐Liss, Inc.