Adoptive transfer of human papillomavirus E7-specific CTL enhances tumor chemoresponse through the perforin/granzyme-mediated pathway.
Adoptive cytotoxic T lymphocyte (CTL) therapy has an important implication in treating cancer patients. Here, we investigate whether adoptive transfer of human papillomavirus (HPV) E7-specific CTL can enhance tumor chemoresponse using an established cervical cancer animal model. Cisplatin-based chemotherapy plus CTL therapy showed an improved therapeutic effectiveness, along with antitumor protective responses to a parental tumor cell rechallenge. Cisplatin treatment dose-dependently increased the expression of Fas, intercellular adhesion molecule (ICAM)-1, and major histocompatibility complex (MHC) class I antigens (Ags) on tumor cells in vitro. However, CTL-expressing FasL failed to improve antitumor activity in vitro and in animals, resulting from nonfunctional Fas expressed on tumor cells. In contrast, ethylene glycol tetraacetic acid (EGTA) treatment blocked increased sensitivity of cisplatin-treated tumor cells to CTL-mediated killing in vitro, suggesting an important role of the perforin/granzyme-mediated pathway for improved therapeutic effectiveness. This notion was further confirmed by perforin knockout animal studies. Thus, this study shows that (i) modulation of Ag (Fas, ICAM-1) expression by tumor cells has little effect on their increased sensitivity to CTL-mediated killing, (ii) improved therapeutic effectiveness is mediated mainly through the perforin/granzyme-mediated tumor killing pathway, and (iii) a combination of chemotherapy and adoptive E7-specific CTL transfer augments antitumor therapeutic activity in vivo. This finding may have important implications for treating HPV-associated cervical cancer.
Sin
Jeong-Im
JI
Department of Microbiology, Catholic University of Daegu, Daegu, Korea. jsin1964@hanmail.net
Kim
Jung-Min
JM
Bae
Sung Hwa
SH
Lee
In Hee
IH
Park
Jong Sup
JS
Ryoo
Hun Mo
HM
D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D054353:Perforin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000378:metabolism*
D050725:Papillomavirus E7 Proteins; D054353:Perforin; D004533:Egtazic Acid; D053804:Granzymes; D002945:Cisplatin