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PD-L2 Landscape and Correlation with Outcome: An Immunomic Analysis.
Anannya Patwari1, Daisuke Nishizaki2, Taylor Jensen3
1MCW Cancer Center and Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, United States.
JCO Oncology Advances
|January 22, 2026
Summary
High programmed death-ligand 2 (PD-L2) expression is linked to better outcomes in patients receiving immunotherapy. This finding highlights PD-L2’s role in cancer immune escape and treatment response.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Programmed death-ligand 1 (PD-L1) and PD-L2 are key ligands in immune evasion by interacting with PD-1 receptors.
- While PD-L1 is well-researched, PD-L2's role in immune checkpoint blockade efficacy remains less understood.
- PD-L2 expression may affect the completeness of PD-1 axis blockade by anti-PD-L1 therapies and influence anti-PD-1 agent activity.
Purpose of the Study:
- To investigate the transcriptomic expression of PD-L2 across various cancer types.
- To explore associations between PD-L2 expression and immunomodulatory variables.
- To determine the prognostic significance of PD-L2 expression in patients with advanced/metastatic cancer.
Main Methods:
- Analysis of PD-L2 transcriptomic expression in a pan-cancer cohort of 514 patients.
- Correlation of PD-L2 expression with immunomodulatory factors like PD-L1, PD-1, CD4, TIM-3, and tumor mutational burden (TMB).
- Evaluation of PD-L2 expression as a prognostic marker for overall survival (OS) and progression-free survival (PFS) in immunotherapy-treated and non-treated patient cohorts.
Main Results:
- High PD-L2 expression (≥75th percentile) was observed in 19.5% of patients and varied across tumor types, being more common in breast cancer.
- High PD-L2 correlated significantly with high PD-L1, PD-1, CD4, TIM-3 RNA levels, and high TMB (≥10 mutations/megabase).
- In immunotherapy-treated patients (n=217), high PD-L2 predicted longer OS (p=0.02) but not PFS; no prognostic value was found in non-immunotherapy patients (n=272).
Conclusions:
- High PD-L2 transcript levels are associated with favorable immune profiles, including high expression of PD-L1, PD-1, CD4, TIM-3, and high TMB.
- Elevated PD-L2 expression correlates with improved overall survival in patients undergoing immune checkpoint blockade therapy.
- PD-L2 warrants further investigation as a potential biomarker for predicting response to immunotherapy.
Keywords:
Immune Checkpoint InhibitorsImmunotherapyNeoplasmsPrecision MedicineProgrammed Cell Death 1 Ligand 2 ProteinMore Related Videos
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