title: 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.
abstract: 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)-α2b 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-α 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.
authors.affiliation: University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Tarhini
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.forename: Yongli
authors.initials: Y
authors.lastname: Shuai
authors.forename: William E
authors.initials: WE
authors.lastname: Gooding
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007167:Immunotherapy; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D016896:Treatment Outcome; D022223:Vaccines, Subunit
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; C483020:ProMune; D051217:Toll-Like Receptor 9; D022223:Vaccines, Subunit; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C520704:tremelimumab