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Genomic and immunologic correlates of LAG-3 expression in cancer
Anshuman Panda1, Jeffrey A Rosenfeld1, Eric A Singer1,2
1Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
Abstract:
Immune checkpoint blockade leads to unprecedented responses in many cancers. Although currently available agents mostly target the PD-1 and CTLA-4 pathways, agents targeting the immune checkpoint protein LAG-3 are under active clinical development, and early clinical data show that LAG-3 expression is a biomarker of response to LAG-3 blockade. To determine which cancers may benefit most from LAG-3 blockade, we performed a pan-cancer analysis of The Cancer Genome Atlas dataset to identify genomic and immunologic correlates of LAG-3 expression. High mutation burden, and expression of exogenous virus (EBV, HPV) or endogenous retrovirus (ERV3-2), were associated with overexpression of LAG-3 in multiple cancers. Although CD8+ T-cell marker (CD8A) and LAG-3 were strongly co-expressed with each other and with PD-L1 in most cancers, there were three notable exceptions: HPV+ head-neck squamous cell cancer, renal cell cancer, and glioblastoma. These results may have important implications for guiding development clinical trials of LAG-3 blockade.
Insights
Immune checkpoint protein LAG-3 (Lymphocyte-Activation Gene 3) blockade shows promise in cancer treatment. This study identified key genomic and immune factors associated with LAG-3 expression across various cancers.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Immune checkpoint blockade therapies, targeting pathways like PD-1 and CTLA-4, have revolutionized cancer treatment.
- Lymphocyte-Activation Gene 3 (LAG-3) is an emerging immune checkpoint target with agents in clinical development.
- LAG-3 expression is a potential biomarker for response to LAG-3 blockade therapies.
Purpose of the Study:
- To conduct a pan-cancer analysis of The Cancer Genome Atlas (TCGA) dataset.
- To identify genomic and immunologic correlates associated with Lymphocyte-Activation Gene 3 (LAG-3) expression.
- To determine which cancer types may benefit most from LAG-3 blockade.
Main Methods:
- Pan-cancer analysis utilizing The Cancer Genome Atlas (TCGA) dataset.
- Investigation of genomic features, including mutation burden and viral expression (EBV, HPV, ERV3-2).
- Analysis of immune cell markers, specifically CD8+ T-cell marker (CD8A) and PD-L1 co-expression with LAG-3.
Main Results:
- High tumor mutation burden and expression of exogenous (EBV, HPV) or endogenous retroviruses (ERV3-2) correlated with increased LAG-3 expression in multiple cancers.
- CD8A and LAG-3 were generally co-expressed with each other and with PD-L1 across most cancer types.
- Notable exceptions to strong CD8A/LAG-3/PD-L1 co-expression were observed in HPV+ head and neck squamous cell carcinoma, renal cell carcinoma, and glioblastoma.
Conclusions:
- Genomic factors like high mutation burden and viral expression are associated with LAG-3 overexpression.
- The co-expression patterns of LAG-3, CD8A, and PD-L1 vary across different cancer types.
- These findings have significant implications for selecting patient populations and guiding clinical trial development for LAG-3 blockade therapies.
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