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Published on: February 7, 2021
A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients
Chuan Li1, Yee Peng Phoon2, Keaton Karlinsey1
1Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT.
Abstract:
Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS "CD8+ TOXPHOS cells." We validated that higher levels of OXPHOS in tumor- and peripheral blood-derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients.
Insights
Researchers identified a specific CD8 T cell type, CD8+ TOXPHOS cells, linked to resistance against immune checkpoint inhibitor (ICI) therapy in melanoma. This discovery offers a new way to predict patient response to ICI treatment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint inhibitor (ICI) therapy has transformed melanoma treatment.
- However, predicting patient response to ICI remains a challenge.
- Developing minimally invasive predictive assays is crucial.
Purpose of the Study:
- To identify a novel immune cell subpopulation in melanoma patients.
- To investigate its association with response to ICI therapy.
- To develop a predictive model for ICI response.
Main Methods:
- Single-cell transcriptomics was employed to analyze CD8 T cells from melanoma patients.
- Characterization of cell subpopulations based on oxidative phosphorylation (OXPHOS) and marker expression (CD38, CD39).
- Validation of findings in tumor and peripheral blood samples.
Main Results:
- A distinct CD8 T cell subpopulation, termed "CD8+ TOXPHOS cells," was identified.
- These cells exhibit high OXPHOS, express CD38 and CD39, and possess exhaustion/cytotoxicity markers.
- Higher levels of CD8+ TOXPHOS cells correlated with resistance to ICI therapy in melanoma.
- A predictive model based on CD8+ TOXPHOS cell transcriptomic profile accurately distinguished responders from non-responders.
Conclusions:
- CD8+ TOXPHOS cells are a key immune population associated with ICI resistance in melanoma.
- These cells can be detected in both tumor tissue and peripheral blood.
- CD8+ TOXPHOS cells represent a potential biomarker for predicting ICI response and a therapeutic target.
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