Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis.
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.
Hill
Seran C
SC
Cancer Research UK Institute for Cancer Studies and Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birhimgham B15 2TA, UK.
Youde
Sarah J
SJ
Man
Stephen
S
Teale
Glyn R
GR
Baxendale
Amanda J
AJ
Hislop
Andrew
A
Davies
Clare C
CC
Luesley
David M
DM
Blom
Anna M
AM
Rickinson
Alan B
AB
Young
Lawrence S
LS
Eliopoulos
Aristides G
AG
D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D030361:Papillomavirus Infections; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000378:metabolism*; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000378:metabolism
D019013:CD40 Antigens; D016328:NF-kappa B; D023201:CD40 Ligand; D020929:Mitogen-Activated Protein Kinase Kinases; D046988:Proteasome Endopeptidase Complex