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. 2021 Feb 16;10(2):406.
doi: 10.3390/cells10020406.

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

Sabino Strippoli  1 , Annarita Fanizzi  2 , Antonio Negri  3 , Davide Quaresmini  1 , Annalisa Nardone  2 , Andrea Armenio  4 , Angela Monica Sciacovelli  1 , Raffaella Massafra  2 , Ivana De Risi  1 , Giacoma De Tullio  3 , Anna Albano  1 , Michele Guida  1
Affiliations

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

Sabino Strippoli et al. Cells. .

Abstract

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.

Keywords: checkpoint inhibitors; double negative T cells; immunotherapy resistance; melanoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Progression-free survival (PFS) of metastatic melanoma patients treated with ipilimumab (orange line) and PD1 inhibitors (blue line); (b) overall survival (OS) of the same population treated with the two class of check-point inhibitors.
Figure 2
Figure 2
(a) Contrasting trends of DNT, CD4+, CD56+ T cells in patients who responded and who did not respond to checkpoint inhibitor therapy. (b) Evidence of statistically significant difference between the change in the number of αβ-DNTs between responders and non-responders among patients with baseline LDH > ULN.
Figure 3
Figure 3
(a) Variation of circulating αβ DNTs and LDH in a single patient receiving ipilimumab at baseline and at first radiological assessment, showing the progression of disease, then 1 and 3 months after a course of brain radiotherapy. (b) Computer tomography scan of lymph node and soft tissue metastases after the completion of four cycles of ipilimumab (upper part of the panel) and three months after a course of brain radiotherapy (lower part of panel) when a remarkable radiological shrinkage was documented as a result of a conceivable abscopal effect.
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