Related Experiment Video
Updated: Sep 12, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Pan-Cancer Landscape of B- and T-Lymphocyte Attenuator: Implications for Potential Immunotherapy Combinations
Daisuke Nishizaki1, Sharon Choi1, Chinmayi Pandya1
1Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, CA.
Purpose:
Cotargetable immune pathways for available immune checkpoint inhibitors (ICIs) may mediate response and mitigate resistance. Immune profiling may provide insights into potential immunotherapy combinations and guide ongoing clinical trials. This study investigated the transcriptomic expression and clinical implications of B- and T-lymphocyte attenuator (BTLA), a promising immune target.
Methods:
Altogether, 514 advanced/metastatic samples (pan-solid cancers) were analyzed using RNA sequencing. Transcriptomic expression was normalized to a reference population of 735 tumors and expressed as percentiles. BTLA, BTLA-related markers (herpes virus entry mediator [HVEM], CD160, LIGHT), and currently targetable immune pathway checkpoints (PD-1, PD-L1, PD-L2, cytotoxic T-cell lymphocyte-4 [CTLA-4], lymphocyte-activation gene 3) as well as clinical outcomes were evaluated.
Results:
High BTLA RNA expression (≥75th percentile) was observed in 19% of tumors (96 of 514). Approximately half of these patients (44 of 96) exhibited higher coexpression (RNA) of targetable checkpoints (cluster analysis). High BTLA expression was independently associated with elevated PD-1, CTLA-4, HVEM, and CD160 RNA levels and with a breast cancer diagnosis. Outcome analysis (Kaplan-Meier) indicated that high BTLA expression correlated with significantly longer survival among ICI recipients in univariable analysis, with a trend in multivariable Cox regression (adjusted hazard ratio, 0.43 [95% CI, 0.17 to 1.08], P = .07). Notably, expression patterns of BTLA, other immune checkpoints, and BTLA-interacting molecules (HVEM, CD160, LIGHT) varied from patient to patient.
Conclusion:
High BTLA transcript expression correlates with high transcript levels of PD-1 and CTLA-4 and with high levels of its ligand HVEM. These findings might support combining anti-PD-1 or anti-CTLA-4 therapy with anti-BTLA. BTLA expression varied across cancers and showed diverse coexpression patterns with other immune markers, suggesting that individual immunomic analysis is needed as part of a precision immunotherapy approach to understanding response and resistance.
Insights
High B- and T-lymphocyte attenuator (BTLA) expression correlates with better survival in patients receiving immune checkpoint inhibitors (ICIs). This suggests BTLA may be a valuable target for novel immunotherapy combinations.
Area of Science:
- Immunology and Cancer Research
- Molecular Oncology
- Translational Medicine
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment.
- Identifying novel cotargetable immune pathways is crucial for improving ICI efficacy and overcoming resistance.
- B- and T-lymphocyte attenuator (BTLA) is a promising immune target with potential roles in immune regulation.
Purpose of the Study:
- To investigate the transcriptomic expression of BTLA in advanced/metastatic solid tumors.
- To evaluate the clinical implications of BTLA expression, including its association with other immune checkpoints and patient survival.
- To explore the potential of BTLA as a target for novel immunotherapy strategies.
Main Methods:
- RNA sequencing was performed on 514 advanced/metastatic solid tumor samples.
- Transcriptomic expression of BTLA, BTLA-related markers (HVEM, CD160, LIGHT), and key immune checkpoints (PD-1, PD-L1, PD-L2, CTLA-4, LAG-3) was analyzed.
- Statistical analyses, including Kaplan-Meier survival and Cox regression, were used to assess correlations with clinical outcomes.
Main Results:
- High BTLA RNA expression (≥75th percentile) was found in 19% of tumors.
- High BTLA expression was associated with elevated PD-1, CTLA-4, HVEM, and CD160 RNA levels, and a breast cancer diagnosis.
- Among ICI recipients, high BTLA expression correlated with significantly longer survival in univariable analysis (trend in multivariable analysis).
Conclusions:
- High BTLA transcript expression is linked to high levels of PD-1, CTLA-4, and its ligand HVEM.
- These findings support the potential of combining anti-PD-1 or anti-CTLA-4 therapies with anti-BTLA agents.
- Individualized immunomic analysis is essential for precision immunotherapy, given the variable expression and coexpression patterns of BTLA and related markers across cancers.
Related Concept Videos
01:27Tumor Immunotherapy
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...