GM-CSF Modulates the Migratory Phenotype of Vaccine-Induced T Cells by Enhancing CXCR3 Expression

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GM-CSF modulates the migratory phenotype of vaccine-induced T cells by enhancing CXCR3 expression Il-Kang Na Carmen Scheibenbogen Ulrich Keilholz Department of Hematology, Oncology and Transfusion Medicine, Charité Berlin, Campus Benjamin Franklin, Germany. Background Selective chemokine receptor Inflammatory Local tissue microenvironment CXCR3 Tumor tissue CCR4 Skin CCR9 Tissue specific dendritic cells Small intestine Aim of the study Analysis of • Expression of chemokine receptors CXCR3 and CCR4 on vaccine-induced T cells. • Influence of GM-CSF as vaccine adjuvant on chemokine receptor expression. Materials & Methods • Patient samples: stage III/ IV melanoma 1) Tyrosinase peptide + KLH + GM-CSF 2 cohorts 2) Tyrosinase peptide + KLH • T cell response assessment by IFNγ flow cytometry analysis Phase I trial of tyrosinase peptide with adjuvants GM-CSF and KLH 50 50 40 40 30 30 Tyr specific 20 20 PBMC 6 10 10 / 10 0 0 before P13 P14 P15 P15 P16 P17 P17 P18 P18 P19 P11 P11 P12 P12 P13 P31 P32 P33 P34 P35 P35 P36 P36 P37 P38 P38 P39 P40 # 2 # 4 T cells Tyr + KLH Tyr + KLH + GM-CSF # 6 ng i 250 250 200 200 150 150 KLH specific IFNg-secret 100 100 50 50 0 0 P21 P22 P23 P24 P25 P26 P27 P28 P29 P30 P31 P32 P33 P34 P35 P36 P37 P38 P39 Patient identification Scheibenbogen et al. 2003 CXCR3 expression on KLH-specific T cells no antigen KLH 25.2 0.02 24.7 0.06 74.7 0.04 75.1 0.2 Tyr + KLH cohort CXCR3 46.6 0.02 46.0 0.09 52.1 0.01 51.9 0.06 Tyr + KLH + GM-CSF cohort IFNγ CXCR3, CCR4 and CCR9 expression on KLH-specific T cells with GM-CSF without GM-CSF with GM-CSF without GM-CSF s n=5 n=6 l l n=8 n=7 e 60 c T 40 s 80 l + l p=0.001 4 e R c 60 20 C T C + 0 40 3 % R C 20 total KLH- total KLH- X CD4+ specific CD4+ specific C 0 T cells T cells T cells T cells % s total KLH- total KLH- l l n=4 n=7 CD4+ specific CD4+ specific e 60 c T cells T cells T cells T cells T 40 + 9 R 20 C C 0 % Follow up of CXCR3 profile of KLH-specific T cells total CD4+ T cells KLH-specific T cells 60 With Without 50 GM-CSF GM-CSF 40 30 20 % CXCR3 + T cells 10 0 1 6 17 1 4 18 time [months] Summary • These results show for the first time in humans that it is possible to modulate chemokine receptor expression on T cells generated by vaccination by modifying the local vaccine milieu. • Immunization protocols that induce T cells expressing CXCR3 may be of considerable value for improvement of immune therapy strategies. Ulrich Keilholz Sandra Bauer Anne Letsch Eckhard Thiel Anne Marie Asemissen Carmen Scheibenbogen Dirk Nagorsen .

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