CCR5+ Myeloid-Derived Suppressor Cells Are Enriched and Activated in Melanoma Lesions

TY - JOUR

T1 - CCR5+ Myeloid-Derived Suppressor Cells Are Enriched and Activated in Melanoma Lesions

AU - Blattner, Carolin

AU - Fleming, Viktor

AU - Weber, Rebekka

AU - Himmelhan, Bianca

AU - Altevogt, Peter

AU - Gebhardt, Christoffer

AU - Schulze, Torsten J

AU - Razon, Hila

AU - Hawila, Elias

AU - Wildbaum, Gizi

AU - Utikal, Jochen

AU - Karin, Nathan

AU - Umansky, Viktor

N1 - ©2017 American Association for Cancer Research.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Accumulation of myeloid-derived suppressor cells (MDSC) in melanoma microenvironment is supported by chemokine receptor/chemokine signaling. Although different chemokines were suggested to be involved in this process, the role of CCR5 and its ligands is not established. Using aRettransgenic mouse melanoma model, we found an accumulation of CCR5+MDSCs in melanoma lesions associated with both increased concentrations of CCR5 ligands and tumor progression. Tumor-infiltrating CCR5+MDSCs displayed higher immunosuppressive activity than their CCR5-counterparts. Upregulation of CCR5 expression on CD11b+Gr1+myeloid cells was inducedin vitroby CCR5 ligands and other inflammatory factors. In melanoma patients, CCR5+MDSCs were enriched at the tumor site and correlated with enhanced production of CCR5 ligands. Moreover, they exhibited a stronger immunosuppressive pattern compared with CCR5-MDSCs. Blocking CCR5/CCR5 ligand interactions increased survival of tumor-bearing mice and was associated with reduced migration and immunosuppressive potential of MDSCs in tumor lesions. Our findings define a critical role for CCR5 in recruitment and activation of MDSCs, suggesting a novel strategy for melanoma treatment.Significance:These findings validate the importance of the CCR5/CCR5 ligand axis not only for MDSC recruitment but also for further activation of their immunosuppressive functions in the tumor microenvironment, with potentially broad therapeutic implications, given existing clinically available inhibitors of this axis.Cancer Res; 78(1); 157-67. ©2017 AACR.

AB - Accumulation of myeloid-derived suppressor cells (MDSC) in melanoma microenvironment is supported by chemokine receptor/chemokine signaling. Although different chemokines were suggested to be involved in this process, the role of CCR5 and its ligands is not established. Using aRettransgenic mouse melanoma model, we found an accumulation of CCR5+MDSCs in melanoma lesions associated with both increased concentrations of CCR5 ligands and tumor progression. Tumor-infiltrating CCR5+MDSCs displayed higher immunosuppressive activity than their CCR5-counterparts. Upregulation of CCR5 expression on CD11b+Gr1+myeloid cells was inducedin vitroby CCR5 ligands and other inflammatory factors. In melanoma patients, CCR5+MDSCs were enriched at the tumor site and correlated with enhanced production of CCR5 ligands. Moreover, they exhibited a stronger immunosuppressive pattern compared with CCR5-MDSCs. Blocking CCR5/CCR5 ligand interactions increased survival of tumor-bearing mice and was associated with reduced migration and immunosuppressive potential of MDSCs in tumor lesions. Our findings define a critical role for CCR5 in recruitment and activation of MDSCs, suggesting a novel strategy for melanoma treatment.Significance:These findings validate the importance of the CCR5/CCR5 ligand axis not only for MDSC recruitment but also for further activation of their immunosuppressive functions in the tumor microenvironment, with potentially broad therapeutic implications, given existing clinically available inhibitors of this axis.Cancer Res; 78(1); 157-67. ©2017 AACR.

KW - Journal Article

U2 - 10.1158/0008-5472.CAN-17-0348

DO - 10.1158/0008-5472.CAN-17-0348

M3 - SCORING: Journal article

C2 - 29089297

VL - 78

SP - 157

EP - 167

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 1

ER -