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Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis

Hill, S C; Youde, S J; Man, S; Teale, G R; Baxendale, A J; Hislop, A; Davies, C C; Luesley, D M; Blom, Anna LU and Rickinson, A B, et al. (2005) In Journal of Immunology 174(1). p.41-50
Abstract
In this study, we describe the expression and function of CD40, a TNF receptor family member, in cervical carcinomas. CD40 was present at very low levels in normal cervical epithelium but was overexpressed in human papillomavirus-infected lesions and advanced squamous carcinomas of the cervix. The stimulation of CD40-positive cervical carcinoma cell lines with soluble CD40L (CD154) resulted in activation of the NF-kappaB and MAPK signaling pathways and up-regulation of cell surface markers and intracellular molecules associated with Ag processing and presentation. Concomitantly, the CD154-induced activation of CD40 in carcinoma cells was found to directly influence susceptibility to CTL-mediated killing. Thus, CD40 stimulation in cervical... (More)
In this study, we describe the expression and function of CD40, a TNF receptor family member, in cervical carcinomas. CD40 was present at very low levels in normal cervical epithelium but was overexpressed in human papillomavirus-infected lesions and advanced squamous carcinomas of the cervix. The stimulation of CD40-positive cervical carcinoma cell lines with soluble CD40L (CD154) resulted in activation of the NF-kappaB and MAPK signaling pathways and up-regulation of cell surface markers and intracellular molecules associated with Ag processing and presentation. Concomitantly, the CD154-induced activation of CD40 in carcinoma cells was found to directly influence susceptibility to CTL-mediated killing. Thus, CD40 stimulation in cervical carcinoma cell lines expressing a TAP-dependent human papillomavirus 16 E6 Ag epitope resulted in their enhanced killing by specific CTLs. However, CD154 treatment of carcinoma cells expressing proteasome-dependent but TAP-independent Ags from the EBV-encoded BRLF1 and BMLF1 failed to increase tumor cell lysis by specific CTLs. Moreover, we demonstrate that chemotherapeutic agents that suppress protein synthesis and reverse the CD40-mediated dissociation of the translational repressor eukaryotic initiation factor 4E-binding protein from the initiation factor eukaryotic initiation factor 4E, such as 5-fluorouracil, etoposide, and quercetin, dramatically increase the susceptibility of cervical carcinoma cells to CD40L-induced apoptosis. Taken together, these observations demonstrate the functional expression of CD40 in epithelial tumors of the cervix and support the clinical exploitation of the CD40 pathway for the treatment of cervical cancer through its multiple effects on tumor cell growth, apoptosis, and immune recognition. (Less)
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Journal of Immunology
volume
174
issue
1
pages
41 - 50
publisher
American Association of Immunologists
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  • pmid:15611226
  • wos:000225852900008
  • scopus:19944419103
ISSN
1550-6606
language
English
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yes
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5c3eecb1-37a3-43e5-965d-2aed20320d55 (old id 258379)
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http://www.jimmunol.org/cgi/content/abstract/174/1/41?ck=nck
date added to LUP
2007-08-03 09:32:00
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2017-07-30 04:41:00
@article{5c3eecb1-37a3-43e5-965d-2aed20320d55,
  abstract     = {In this study, we describe the expression and function of CD40, a TNF receptor family member, in cervical carcinomas. CD40 was present at very low levels in normal cervical epithelium but was overexpressed in human papillomavirus-infected lesions and advanced squamous carcinomas of the cervix. The stimulation of CD40-positive cervical carcinoma cell lines with soluble CD40L (CD154) resulted in activation of the NF-kappaB and MAPK signaling pathways and up-regulation of cell surface markers and intracellular molecules associated with Ag processing and presentation. Concomitantly, the CD154-induced activation of CD40 in carcinoma cells was found to directly influence susceptibility to CTL-mediated killing. Thus, CD40 stimulation in cervical carcinoma cell lines expressing a TAP-dependent human papillomavirus 16 E6 Ag epitope resulted in their enhanced killing by specific CTLs. However, CD154 treatment of carcinoma cells expressing proteasome-dependent but TAP-independent Ags from the EBV-encoded BRLF1 and BMLF1 failed to increase tumor cell lysis by specific CTLs. Moreover, we demonstrate that chemotherapeutic agents that suppress protein synthesis and reverse the CD40-mediated dissociation of the translational repressor eukaryotic initiation factor 4E-binding protein from the initiation factor eukaryotic initiation factor 4E, such as 5-fluorouracil, etoposide, and quercetin, dramatically increase the susceptibility of cervical carcinoma cells to CD40L-induced apoptosis. Taken together, these observations demonstrate the functional expression of CD40 in epithelial tumors of the cervix and support the clinical exploitation of the CD40 pathway for the treatment of cervical cancer through its multiple effects on tumor cell growth, apoptosis, and immune recognition.},
  author       = {Hill, S C and Youde, S J and Man, S and Teale, G R and Baxendale, A J and Hislop, A and Davies, C C and Luesley, D M and Blom, Anna and Rickinson, A B and Young, L S and Eliopoulos, A G},
  issn         = {1550-6606},
  language     = {eng},
  number       = {1},
  pages        = {41--50},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis},
  volume       = {174},
  year         = {2005},
}