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Updated: Mar 12, 2026
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and
Ludmila Danilova1,2,3, Hao Wang1, Joel Sunshine4
1Department of Oncology, The Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287.
Abstract:
Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade has led to remarkable and durable objective responses in a number of different tumor types. A better understanding of factors associated with the PD-1/PD-L axis expression is desirable, as it informs their potential role as prognostic and predictive biomarkers and may suggest rational treatment combinations. In the current study, we analyzed PD-L1, PD-L2, PD-1, and cytolytic activity (CYT) expression, as well as mutational density from melanoma and eight other solid tumor types using The Cancer Genome Atlas database. We found that in some tumor types, PD-L2 expression is more closely linked to Th1/IFNG expression and PD-1 and CD8 signaling than PD-L1 In contrast, mutational load was not correlated with a Th1/IFNG gene signature in any tumor type. PD-L1, PD-L2, PD-1, CYT expression, and mutational density are all positive prognostic features in melanoma, and conditional inference modeling revealed PD-1/CYT expression (i.e., an inflamed tumor microenvironment) as the most impactful feature, followed by mutational density. This study elucidates the highly interdependent nature of these parameters, and also indicates that future biomarkers for anti-PD-1/PD-L1 will benefit from tumor-type-specific, integrated, mRNA, protein, and genomic approaches.
Insights
Understanding the PD-1/PD-L1 axis is key for cancer immunotherapy. This study reveals PD-L2 is linked to immune signaling, and PD-1/CYT expression is a strong prognostic marker in melanoma.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade shows promise in cancer treatment.
- Understanding factors influencing PD-1/PD-L1 expression is crucial for biomarker development and combination therapies.
Purpose of the Study:
- To analyze PD-L1, PD-L2, PD-1, and cytolytic activity (CYT) expression, alongside mutational density in melanoma and other solid tumors.
- To investigate the relationship between these factors and their prognostic and predictive potential.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) database for analysis.
- Examined gene expression (PD-L1, PD-L2, PD-1, CYT, IFNG, CD8) and mutational density.
- Applied conditional inference modeling for prognostic feature identification.
Main Results:
- PD-L2 expression correlated more strongly with Th1/IFNG and PD-1/CD8 signaling than PD-L1 in certain tumors.
- Mutational load did not correlate with Th1/IFNG gene signature across tumor types.
- PD-1/CYT expression (inflamed tumor microenvironment) emerged as the most impactful prognostic feature in melanoma, followed by mutational density.
Conclusions:
- PD-1/PD-L1 axis expression is complex and interdependent with immune signaling and tumor mutational landscape.
- Integrated, tumor-type-specific approaches combining mRNA, protein, and genomic data are essential for future biomarker development for anti-PD-1/PD-L1 therapies.
