Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions.
BACKGROUND
Persistent high risk HPV infection can lead to cervical cancer, the second most common malignant tumor in women worldwide. NK cells play a crucial role against tumors and virus-infected cells through a fine balance between activating and inhibitory receptors. Expression of triggering receptors NKp30, NKp44, NKp46 and NKG2D on NK cells correlates with cytolytic activity against tumor cells, but these receptors have not been studied in cervical cancer and precursor lesions. The aim of the present work was to study NKp30, NKp46, NKG2D, NKp80 and 2B4 expression in NK cells from patients with cervical cancer and precursor lesions, in the context of HPV infection.


METHODS
NKp30, NKp46, NKG2D, NKp80 and 2B4 expression was analyzed by flow cytometry on NK cells from 59 patients with cervical cancer and squamous intraepithelial lesions. NK cell cytotoxicity was evaluated in a 4 hour CFSE/7-AAD flow cytometry assay. HPV types were identified by PCR assays.


RESULTS
We report here for the first time that NK cell-activating receptors NKp30 and NKp46 are significantly down-regulated in cervical cancer and high grade squamous intraepithelial lesion (HGSIL) patients. NCRs down-regulation correlated with low cytolytic activity, HPV-16 infection and clinical stage. NKG2D was also down-regulated in cervical cancer patients.


CONCLUSIONS
Our results suggest that NKp30, NKp46 and NKG2D down-regulation represent an evasion mechanism associated to low NK cell activity, HPV-16 infection and cervical cancer progression.
Garcia-Iglesias
Trinidad
T
Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada No 950, Colonia Independencia, Guadalajara, Jalisco, Mexico. tgarcia@cucs.udg.mx
Del Toro-Arreola
Alicia
A
Albarran-Somoza
Benibelks
B
Del Toro-Arreola
Susana
S
Sanchez-Hernandez
Pedro E
PE
Ramirez-Dueñas
Maria Guadalupe
MG
Balderas-Peña
Luz Ma Adriana
LM
Bravo-Cuellar
Alejandro
A
Ortiz-Lazareno
Pablo C
PC
Daneri-Navarro
Adrian
A
D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000821:virology; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D052162:Human papillomavirus 16 / Q000276:immunology / Q000302:isolation & purification; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis*; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000096:biosynthesis*; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000096:biosynthesis*; D030361:Papillomavirus Infections / Q000276:immunology / Q000821:virology; D011971:Receptors, Immunologic / Q000096:biosynthesis; D055607:Receptors, Natural Killer Cell / Q000096:biosynthesis; D000071176:Signaling Lymphocytic Activation Molecule Family; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000821:virology
D015703:Antigens, CD; C084093:CD244 protein, human; C431711:KLRF1 protein, human; C527085:KLRK1 protein, human; D037181:Lectins, C-Type; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D000071176:Signaling Lymphocytic Activation Molecule Family