Lectin-Like Transcript 1 (LLT1) Checkpoint: A Novel Independent Prognostic Factor in HPV-Negative Oropharyngeal Squamous Cell Carcinoma
Mario Sanchez-Canteli,
Francisco Hermida-Prado,
Christian Sordo-Bahamonde,
Irene Montoro-Jiménez,
Esperanza Pozo-Agundo,
Eva Allonca,
Aitana Vallina-Álvarez,
César Álvarez-Marcos,
Segundo Gonzalez,
Juana M. García-Pedrero,
Juan P. Rodrigo
Affiliations
Mario Sanchez-Canteli
Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
Francisco Hermida-Prado
Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
Christian Sordo-Bahamonde
Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33006 Oviedo, Spain
Irene Montoro-Jiménez
Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
Esperanza Pozo-Agundo
Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
Eva Allonca
Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
Aitana Vallina-Álvarez
Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33006 Oviedo, Spain
César Álvarez-Marcos
Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
Segundo Gonzalez
Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33006 Oviedo, Spain
Juana M. García-Pedrero
Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
Juan P. Rodrigo
Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
Lectin-like transcript 1 (LLT1) expression by tumor cells contributes to immune evasion, thereby emerging as a natural killer (NK) cell-mediated immunotherapeutic target. This study is the first to investigate LLT1 expression (encoded by CLEC2D gene) in head and neck cancers to ascertain its impact on patient prognosis. LLT1 expression was analyzed by immunohistochemistry in a homogeneous cohort of human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinomas (OPSCC), and correlated with clinical data. Results were further validated using transcriptomic data from the TCGA database. Tumoral LLT1 expression was detected in 190/221 (86%) OPSCC specimens, whereas normal pharyngeal epithelium was negative. Patients harboring LLT1-positive tumors showed significantly lower disease-specific (DSS) and overall survival (OS) (p = 0.049 and p = 0.036, respectively, log-rank test). High density of LLT1-positive tumor-infiltrating lymphocytes (TIL) was also frequently detected in 160 (73%) OPSCC samples, and significantly associated with better DSS and OS (p p = 0.007, respectively). Multivariate Cox analysis further revealed that tumoral LLT1 expression and infiltration of LLT1-positive TIL were independent prognostic factors for DSS and OS. CLEC2D mRNA levels are also significantly increased in primary tumors compared to normal tissue. Strikingly, the prognostic impact of CLEC2D mRNA levels varied depending on HPV status in OPSCC, and among distinct cancer types. CLEC2D expression was significantly correlated with NK cell infiltration using the MCP-counter model. These findings uncover LLT1/CLEC2D as an independent prognostic factor in HPV-negative OPSCC, and a potential novel target for immunotherapy.
