Related Experiment Video
Updated: Jun 13, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Differences in Co-Expression of T Cell Co-Inhibitory and Co-Stimulatory Molecules with PD-1 Across Different Human
Ahmad A Tarhini1, Dale Hedges2, Aik Choon Tan3
1Departments of Cutaneous Oncology and Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Purpose:
The promise of immune checkpoint inhibitor (ICI) therapy underlines the importance of comprehensively investigating the rationale for combinations with diverse immune modulators across different cancer types. Given the progress made with PD1 blockade to date, we examined mRNA co-expression levels of PD-1 with 13 immune checkpoints, including co-inhibitory receptors (LAG3, CTLA4, PD-L1, TIGIT, TIM3, VISTA, BTLA) and co-stimulatory molecules (CD28, OX40, GITR, CD137, CD27, HVEM), using RNA-Seq by Expectation-Maximization (RSEM).
Methods:
We analyzed real-world clinical and transcriptomic data from the Total Cancer Care Protocol (NCT03977402) and Avatar® project of patients with cancer treated within the Oncology Research Information Exchange Network (ORIEN) network. Using anti-PD1 as a backbone, we intended to investigate the rationale for combinations in different cancers. Pearson's R coefficients and associated P-values were calculated using SciPy 1.7.0.
Results:
The co-expression of PD1 with 13 immune checkpoints and PD-L1 varies across selected malignancies included. In cutaneous melanoma, PD1 expression correlated significantly with four co-inhibitory receptors (LAG3, TIM3, TIGIT, VISTA) and one co-stimulatory molecule (CD137). In urothelial carcinoma, PD1 expression significantly correlated with four co-inhibitory (TIGIT, CTLA4, LAG3, VISTA) and four co-stimulatory (OX40, CD27, CD137, HVEM) molecules. In pancreatic adenocarcinoma, only CD28 showed a significant correlation with PD1 expression. No significant correlations with PD1 expression were found in the ovarian cancer cohort. Notably, melanoma and urothelial carcinoma exhibited a dominant co-expression of co-inhibitory molecules with PD1, indicative of exhausted T cells, in contrast to the co-stimulatory molecule dominance in ovarian and pancreatic cancers, suggesting less differentiated T cells.
Conclusions:
Our findings highlight the potential for diverse combination strategies in immunotherapy, particularly with PD1 blockade, across various cancers.
Insights
Investigating PD-1 (programmed cell death protein 1) co-expression with immune checkpoints reveals varied combination rationales for immunotherapy. Different cancers show distinct patterns of co-inhibitory and co-stimulatory molecule expression, guiding tailored treatment strategies.
Area of Science:
- Immunology and Oncology
- Cancer Genomics and Transcriptomics
- Translational Cancer Research
Background:
- Immune checkpoint inhibitor (ICI) therapy, particularly PD-1 blockade, shows significant promise in cancer treatment.
- Understanding the interplay between PD-1 and other immune checkpoints is crucial for optimizing combination immunotherapies.
- Diverse cancer types may benefit from distinct combinations of immune modulators.
Purpose of the Study:
- To examine the mRNA co-expression levels of PD-1 with 13 immune checkpoints (co-inhibitory and co-stimulatory molecules).
- To investigate the rationale for combining PD-1 blockade with other immune modulators across different cancer types.
- To analyze real-world clinical and transcriptomic data from cancer patients.
Main Methods:
- Analysis of mRNA co-expression using RNA-Seq by Expectation-Maximization (RSEM).
- Utilized real-world clinical and transcriptomic data from the Total Cancer Care Protocol and Avatar® project.
- Calculated Pearson's R coefficients and P-values using SciPy 1.7.0 to assess correlations.
Main Results:
- PD-1 co-expression patterns with immune checkpoints varied significantly across malignancies.
- Melanoma and urothelial carcinoma showed dominant co-expression of co-inhibitory molecules with PD-1, suggesting T-cell exhaustion.
- Ovarian and pancreatic cancers displayed co-expression patterns favoring co-stimulatory molecules, indicating less differentiated T cells.
Conclusions:
- Findings support diverse combination strategies for PD-1 blockade immunotherapy.
- The distinct co-expression profiles across cancer types provide a basis for tailored combination therapies.
- Further investigation into these combinations can enhance treatment efficacy in various malignancies.
Related Concept Videos
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...
01:27Tumor Immunotherapy