Lectin-Like Transcript 1 (LLT1) Checkpoint: A Novel Independent Prognostic Factor in HPV-Negative Oropharyngeal Squamous Cell Carcinoma.

Irene Montoro-Jiménez,Juana M García-Pedrero,Mario Sanchez-Canteli,Eva Allonca,Aitana Vallina-Álvarez,Segundo Gonzalez,Francisco Hermida-Prado,César Álvarez-Marcos,Esperanza Pozo-Agundo,Juan P Rodrigo,Christian Sordo-Bahamonde

doi:10.3390/biomedicines8120535

Abstract

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 < 0.001 and 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.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is the most frequent malignancy in the head and neck region, and the sixth most commonly diagnosed cancer [1]
Lectin-like transcript 1 (LLT1) immunostaining was successfully evaluated in 221 (92%) out of 241 human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinomas (OPSCC); tumor samples with inadequate tissue integrity and/or tumor representability were excluded from the evaluation
We found that patients with LLT1-negative tumors and high density of LLT1-positive tumor-infiltrating lymphocytes (TIL) (LLT1tum −/LLT1 TIL high) showed the highest survival rates, whereas those patients with LLT1-positive tumors and low density of LLT1-positive TIL

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is the most frequent malignancy in the head and neck region, and the sixth most commonly diagnosed cancer [1]. New biomarkers and/or therapeutic targets are needed to improve the prognosis of these neoplasms. HNSCC is a highly complex disease that arises at various anatomical locations (oral cavity, oropharynx, hypopharynx, and larynx), thereby widely differing in tumor biology, etiology (tobacco and/or HPV infection), clinical behavior, and response to treatment [2]. Taking this into consideration, the study of these tumors should involve homogeneous cohorts of patients; it is advisable to focus on specific tumor locations and similar etiologic factors [3].

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Conclusion