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

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.

Aging modifies endometrial dendritic cell function and unconventional double negative T cells in the human genital mucosa

“…The origin and function of DN T cells in humans is poorly defined, and may include multiple cells with different origins [19]. Further, in humans, DN T cells have been mostly studied in pathological conditions, such as solid tumors (melanoma), transplantation and autoimmune diseases [19][20][21], but little is known about tissue distribution and function in the steady state. Two recent studies described the presence of Mucosal-associated invariant T cells (MAIT) in the endometrium and cervicovaginal tissues, which represents a subset of unconventional DN T cell population with antimicrobial properties [22,23].…”

Exosomes in malignant pleural effusion from lung cancer patients impaired the cytotoxicity of double-negative T cells

“…In addition, we found that the increase in DNT cells in MPE was significantly positively related to LDH, a disease progression marker of lung cancer [22] . The decrease in DNT cells was associated with improvements in melanoma patients [23] . Therefore, we inferred that the increased frequency of DNT cells in MPE may be a sign of tumor exacerbation.…”

“…The combined therapy of CEACAM1/PD-1 blockade and adoptive DNT cell transfer in lung cancers warrants further research. However, DNT cells in blood were decreased in melanoma patients responsive to checkpoint therapy [23] , suggesting that the fluctuation of DNT cells should be monitored in the combined therapy of CEACAM1/PD-1 blockade against lung cancer patients.…”

Thyroid Cancer Screening Using Tumor-Associated DN T Cells as Immunogenomic Markers

“…Since we are proposing DN T-cell expansion as a criterion for solid tumor malignancy, awareness that they may be markedly expanded in some rare blood cancers ( 35) is important to avoid misdiagnosis if solid and blood cancers were to coexist. DN T dominance was also found in cytofluorimetric analyses of tissues from many tumor types such as melanomas, renal cell carcinoma, glioblastoma (36), and melanoma-invaded lymph nodes compared to negative lymph nodes (37). De Tullio et al (38) reported that in Hodgkin's lymphoma, ab-DN Ts were significantly increased as compared with other histotypes, suggesting an important role in the development and progression of Hodgkin's lymphoma.…”