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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma
Wei-Wei Deng1, Liang Mao1, Guang-Tao Yu1
1The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University , Wuhan, China.
Abstract:
Immunotherapy with immune checkpoint molecule-specific monoclonal antibody have obtained encouraging results from preclinical studies and clinical trials, which promoted us to explore whether this kind of immunotherapy could be applicable to head and neck squamous cell carcinoma (HNSCC). Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint control protein that negatively regulates T cells and immune response. Here, using the human tissue samples, we report these findings that LAG-3 is overexpressed on tumor-infiltrating lymphocytes (TILs; p < 0.001) and its overexpression correlates with the high pathological grades, lager tumor size and positive lymph node status in human primary HNSCC. Survival analysis identifies LAG-3 as a prognostic factor independent of tumor size and pathological grades for primary HNSCC patients with negative lymph node status (p = 0.014). Study in immunocompetent genetically defined HNSCC mouse model reports that LAG-3 is upregulated on CD4+ T cells, CD8+ T cells and CD4+Foxp3+ regulatory T cells (Tregs). In vivo study, administration of LAG-3-specific antibody retards tumor growth in a way associated with enhanced systemic antitumor response by potentiating the antitumor response of CD8+ T cells and decreasing the population of immunosuppressive cells. Taken together, our results offer a preclinical proof supporting the immunomodulatory effects of LAG-3 and suggest a potential therapeutic target of immunotherapy for HNSCC.
Insights
Immune checkpoint therapy targeting Lymphocyte Activation Gene-3 (LAG-3) shows promise for head and neck squamous cell carcinoma (HNSCC). LAG-3 overexpression in HNSCC correlates with poor prognosis, and blocking it enhances anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Translational Research
Background:
- Immune checkpoint inhibitors have shown success in various cancers.
- Lymphocyte-activation gene-3 (LAG-3) is an immune checkpoint protein that regulates T-cell responses.
- The potential of LAG-3-targeted immunotherapy in head and neck squamous cell carcinoma (HNSCC) remains largely unexplored.
Purpose of the Study:
- To investigate the role and therapeutic potential of LAG-3 in HNSCC.
- To determine if LAG-3 overexpression correlates with clinicopathological features and prognosis in HNSCC patients.
- To evaluate the efficacy of anti-LAG-3 antibody therapy in a preclinical HNSCC model.
Main Methods:
- Analysis of LAG-3 expression in human HNSCC tissue samples.
- Correlation of LAG-3 expression with pathological grades, tumor size, and lymph node status.
- Survival analysis in HNSCC patients.
- Evaluation of LAG-3 expression on immune cells in a genetically defined HNSCC mouse model.
- Assessment of anti-tumor efficacy of a LAG-3-specific antibody in vivo.
Main Results:
- LAG-3 was significantly overexpressed on tumor-infiltrating lymphocytes in HNSCC.
- Overexpression correlated with higher pathological grades, larger tumor size, and positive lymph node status.
- LAG-3 served as an independent prognostic factor for HNSCC patients with negative lymph node status.
- LAG-3 was upregulated on CD4+, CD8+ T cells, and regulatory T cells (Tregs) in the HNSCC mouse model.
- Anti-LAG-3 antibody treatment retarded tumor growth by enhancing CD8+ T cell responses and reducing immunosuppressive cells.
Conclusions:
- LAG-3 is a significant biomarker and potential therapeutic target in HNSCC.
- Targeting LAG-3 with monoclonal antibodies can enhance systemic anti-tumor immunity.
- These findings provide preclinical support for developing LAG-3-based immunotherapies for HNSCC.
