Differing Patterns of Circulating Regulatory T Cells and Myeloid-derived Suppressor Cells in Metastatic Melanoma Patients Receiving Anti-CTLA4 Antibody and Interferon-α or TLR-9 Agonist and GM-CSF With Peptide Vaccination

Changes in the biomarkers of host suppressor immune response were evaluated in patients with melanoma enrolled in 2 trials. Two similar cohorts of patients participating in the 2 studies were evaluated. The first (IFN/treme) tested interferon (IFN)-alpha 2b and tremelimumab in metastatic melanoma and reported a response rate of 24%, 6.4 months median progression-free survival, and 21 months median overall survival. The second [toll-like receptor 9 (TLR)/GM] tested vaccination with MART-1, gp100, tyrosinase given with TLR-9 agonist and granulocyte-macrophage colony-stimulating factor and reported 9% response rate, median progression-free survival of 1.9 months, and median overall survival of 13.4 months. We monitored circulating T regulatory cells (T-reg) and myeloid-derived suppressor cells (MDSC) utilizing multicolor flow cytometry. In IFN/treme, changes in circulating T-reg and MDSC were compared between baseline, day 29 (end of IFN-alpha induction) and day 85 (1 course). The CD4(+) CD25hi(+) CD39(+) T-reg percentage was increased most at day 85 (P=0.018) and less significantly at day 29 (P=0.09). There was a decrease in the percentage of MDSC populations taken in aggregate, which was most significant for monocytic MDSC (HLA-DR+ low/CD14(+)) at day 29 (P<0.0001) and day 85 (P=0.001). In TLR-9/GM, changes in T-reg and MDSC were compared between baseline and day 50 (4 vaccinations) and day 90 (8 vaccinations). There were no significant changes in T-reg or MDSC, except for a trend towards decreased (HLA-DR+ low/CD14(+)) MDSC at day 50 (P=0.07). Therefore, IFN/treme significantly downregulated MDSC suggesting a role on the significant clinical activity observed in this trial. T-reg findings suggest that IFN/treme induced clinically significant antitumor responses by inhibiting CTLA4 suppressive effects on T effectors, and less so by affecting T-reg.