Anti-LAG-3 Immunotherapy Potentiates Potent Antitumor Immune Response in HNSCC

Objectives: Immune checkpoints, which limited the overactive immune response in normal immune system, were exploited to evade the host immune system in the tumor microenvironment. Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint control protein that negatively regulates T cells and immune response. The objective of this study is to determine the clinical significance of LAG-3 in patient of human head and neck squamous cell carcinoma (HNSCC) and explore the role of LAG-3 in HNSCC mouse model.
Methods: The expression of LAG-3 in HNSCC tissue was determined by immunohistochemistry. Both univariate and multivariate analysis were used to assess the association between LAG-3 and the patient’s survival. Study in vivo was to examine the immunoregulatory function of LAG-3 in immunocompetent genetically defined HNSCC mouse model.
Results: The expression of LAG-3 on tumor infiltrating lymphocytes was (TILs) is upregulated (P < 0.001), and its overexpression is associated with pathological characteristic (grades, tumor size and lymph node status) in human primary HNSCC (n=122). Highly expression of LAG-3 is identified as an independent prognosis factor in primary HNSCC patients without lymph node metastasis (P = 0.014). Study in transgenic HNSCC mouse model reveals that LAG-3 is significantly upregulated on T cells (CD4⁺, CD8⁺, regulatory T cells) but not myeloid cells during tumor progression. Treatment with anti-LAG-3 antibody restrains the tumorigenesis by strengthening immune reaction with the enhancement of CD8⁺ T cell-mediated anti-tumor response and the decrease population of the immunosuppressive cells.
Conclusions: We identify LAG-3 to be a potential prognostic indicator for HNSCC without lymph node metastasis and LAG-3 blockade significantly decreases tumorigenicity and reinvigorates immune response in HNSCC mouse model. These results allow for the speculation that LAG-3 may be a potential target for immunotherapy in HNSCC.