CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis.
Patients with human papillomavirus (HPV)-related oropharyngeal tumors display improved prognosis. The biological basis of this tumor phenotype is poorly understood. We investigated whether increased lymphocyte infiltrate in HPV-positive oropharyngeal squamous cell carcinomas could account for better prognosis. We previously identified, in an Affymetrix GeneChip analysis of 83 HPV-unrelated and 11 HPV-related squamous cell carcinoma of the oropharynx, several candidate genes, including CD8α and CD3ζ. Their expression was validated in this study by qRT-PCR on an independent clinical series of 144 oropharyngeal tumors. Immunohistochemical staining of tumor specimens was performed to evaluate infiltration of tumor stroma by CD8+ and CD4+ lymphocytes. The prognostic value of CD8α and CD3ζ expression levels was measured by Kaplan-Meier and Cox regression model analyses. Immune response-related signaling pathways were found to be deregulated in HPV-positive oropharyngeal tumors. Expression of CD8α, CD3ζ, granzyme K, CD28 and integrin αL RNAs was upregulated in HPV-positive lesions when compared with HPV-unrelated tumors (p < 0.05). Stroma of HPV-positive tumors was frequently and strongly infiltrated by CD8α- and CD3ζ-positive T cells. CD8α RNA expression correlated with both improved global (Kaplan-Meier; p = 0.005; Cox regression: p = 0.003) and disease-free (Cox regression: p = 0.04) survival. CD3ζ RNA expression correlated with improved overall survival (Cox regression: p = 0.024). These results suggest that an increased cytotoxic T-cell-based antitumor immune response is involved in improved prognosis of patients with HPV-positive tumors.
Laboratoire de Biologie Tumorale, EA3430, Centre Régional de Lutte Contre le Cancer Paul Strauss, 3 Rue de la Porte de l'Hôpital, Strasbourg, France. ajung@strasbourg.unicancer.fr
Alain C
AC
Jung
Sébastien
S
Guihard
Sylvie
S
Krugell
Sonia
S
Ledrappier
Alexandra
A
Brochot
Véronique
V
Dalstein
Sylvie
S
Job
Aurélien
A
de Reynies
Georges
G
Noël
Bohdan
B
Wasylyk
Christine
C
Clavel
Joseph
J
Abecassis
D052685:Alphapapillomavirus / Q000235:genetics; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000821:virology; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D009959:Oropharyngeal Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000821:virology; D030361:Papillomavirus Infections / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000821:virology; D011379:Prognosis; D016016:Proportional Hazards Models; D012044:Regression Analysis; D059467:Transcriptome; D059016:Tumor Microenvironment
D017252:CD3 Complex; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D009856:Oncogene Proteins, Viral