Examining the Relationship between Circulating CD4- CD8- Double-Negative T Cells and Outcomes of Immuno-Checkpoint Inhibitor Therapy-Looking for Biomarkers and Therapeutic Targets in Metastatic Melanoma
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Updated: Nov 15, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Sabino Strippoli1, Annarita Fanizzi2, Antonio Negri3
1Rare Tumors and Melanoma Unit, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy.
Background:
The role of circulating CD4-/CD8- double-negative T cells (DNTs) in the immune response to melanoma is poorly understood, as are the effects of checkpoint inhibitors on T cell subpopulations.
Methods:
We performed a basal and longitudinal assessment of circulating immune cells, including DNTs, in metastatic melanoma patients treated with checkpoint blockade in a single-center cohort, and examined the correlations levels of immune cells with clinical features and therapy outcomes.
Results:
Sixty-eight patients (48 ipilimumab, 20 PD1 inhibitors) were enrolled in the study. Our analysis indicated that better outcomes were associated with normal LDH, fewer than three metastatic sites, an ECOG performance status of 0, M1a stage, lower WBC and a higher lymphocyte count. The increase in lymphocyte count and decrease of DNTs were significantly associated with the achievement of an overall response. The median value of DNT decreased while the CD4+ and NK cells increased in patients that responded to treatment compare to those who did not respond to treatment.
Conclusions:
DNT cells change during treatment with checkpoint inhibitors and may be adept at sensing the immune response to melanoma. The complementary variation of DNT cells with respect to CD4+ and other immune actors may improve the reliability of lymphocyte assessment. Further investigation of DNT as a potential target in checkpoint inhibitor resistant melanoma is warranted.
Insights
Changes in CD4-/CD8- double-negative T cells (DNTs) correlate with melanoma treatment response. A decrease in DNTs and increase in lymphocytes indicate a positive response to checkpoint inhibitors.
Area of Science:
- Immunology
- Oncology
Background:
- The role of circulating CD4-/CD8- double-negative T cells (DNTs) in melanoma immunity is unclear.
- Effects of checkpoint inhibitors on T cell subsets need further investigation.
Purpose of the Study:
- To assess circulating immune cells, including DNTs, in metastatic melanoma patients receiving checkpoint blockade.
- To correlate immune cell levels with clinical features and treatment outcomes.
Main Methods:
- Longitudinal analysis of immune cells in 68 metastatic melanoma patients treated with ipilimumab or PD1 inhibitors.
- Correlation of immune cell counts with clinical parameters and response to therapy.
Main Results:
- Better outcomes linked to normal LDH, fewer metastases, good ECOG status, M1a stage, lower WBC, and higher lymphocyte count.
- Increased lymphocyte count and decreased DNTs correlated with overall response.
- Responders showed decreased DNTs and increased CD4+ and NK cells compared to non-responders.
Conclusions:
- DNT cell levels change during checkpoint inhibitor therapy and may reflect melanoma immune response.
- Complementary variations of DNTs with other immune cells could enhance lymphocyte assessment reliability.
- DNTs warrant further investigation as potential targets in checkpoint inhibitor-resistant melanoma.
