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 a transgenic 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 CD11bGr1 myeloid cells was induced by 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. 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. .

Cells of hematopoietic origin can be subdivided into cells of the lymphoid lineage and those of the myeloid lineage, among which are myeloid-derived suppressor cells (MDSCs). The MDSCs can be further divided into CD11bLy6GLy6C monocytic (Mo) MDSCs and CD11bLy6GLy6C polymorphonuclear (PMN) MDSCs. Both subtypes support tumor growth and suppress anti-tumor immunity. Their accumulation at the tumor site includes mobilization from the bone marrow to the blood followed by colonization at the tumor site. The present study examines the mechanism by which PMN-MDSCs are mobilized from the BM to the blood to later accumulate at the tumor site. We show that the chemokine receptor CCR5 is a key driver of this event. We also show that, beyond chemoattraction, the interaction between CCR5 and its ligands promotes the proliferation of CCR5 PMN-MDSCs at the BM and, later, potentiates their immune-suppressive activities at the tumor site in part by inducing arginase-1.

Background HIV Pre-exposure prophylaxis (PrEP) is the regular use of antiretroviral medication by people who are not infected with HIV to prevent seroconversion. Israel approved PrEP for continuous use in 2017, and Israeli Health Maintenance Organizations (HMO) offered PrEP with a copayment to eligible members. Methodology This retrospective cohort study included all people who were dispensed PrEP between September 2017 to June 2019 in the second largest HMO in Israel. Statistical analysis, including Kaplan Meier, was conducted to evaluate user PrEP purchase, adherence to medical follow-up, and clinical outcomes. Results In total, a cohort of 757 PrEP users were followed for 657.8 person-years. All but one user were male; median age was 35 years. At baseline, 0.8% had gonorrhea and 1.5% had chlamydia infections and 4.4% had recent syphilis infection. Continuous use of PrEP (without interruption/discontinuation) was observed in 29.9%, while 39.9% interrupted and 30.3% discontinued use. Median time to first interruption/discontinuation was 4.0 months. At 6–12 months after initiation, 79.8% of users had a documented HIV test, 77.3% a Chlamydia-Gonorrhea panel, and 78.9% a creatinine test. There was one new case of HIV among the cohort, five months after PrEP discontinuation. Estimated first-year infection rates were 5.0%, 8.6% and 6.8% for gonorrhea, chlamydia and first-time syphilis, respectively. Conclusions This study shows heterogeneous PrEP purchase patterns and required medical follow-up, and an increase in STIs among consistent PrEP users. Improving adherence to recommended medical follow-up during PrEP use is essential in PrEP’s integration into Israel’s national HIV prevention strategy.

<div>Abstract<p>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 a <i>Ret</i> transgenic 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 induced <i>in vitro</i> by 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.</p><p><b>Significance:</b> 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. <i>Cancer Res; 78(1); 157–67. ©2017 AACR</i>.</p></div>

<div>Abstract<p>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 a <i>Ret</i> transgenic 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 induced <i>in vitro</i> by 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.</p><p><b>Significance:</b> 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. <i>Cancer Res; 78(1); 157–67. ©2017 AACR</i>.</p></div>