Vemurafenib reverses immunosuppression by myeloid derived suppressor cells

Abstract

Myeloid derived suppressor cells (MDSCs) suppress innate and adaptive immunity, thereby limiting anti‐tumor immune responses in cancer patients. In patients with advanced melanoma, the phenotype and function of MDSCs remains controversial. In our study, we further explored two distinct subpopulations of MDSCs and investigated the impact of Vemurafenib on these cells. Flow cytometry analysis revealed that in comparison to healthy donors and patients with localized disease, PBMCs from patients with metastatic melanoma showed an increased frequency of CD14+HLA‐DR−/low monocytic MDSCs (moMDSCs) and of a previously unrecognized population of CD14−CD66b+Arginase1+ granulocytic MDSCs (grMDSCs). In vitro, both populations suppressed autologous T‐cell proliferation, which was tested in CFSE‐based proliferation assays. Vemurafenib treatment of melanoma patients reduced the frequency of both moMDSCs and grMDSCs. According to our in vivo finding, conditioned medium (CM) from Vemurafenib treated melanoma cells was less active in inducing moMDSCs in vitro than CM from untreated melanoma cells. In conclusion, patients with advanced melanoma show increased levels of moMDSCs, and of a population of CD14−CD66b+Arginase1+ grMDSCs. Both MDSCs are distinct populations capable of suppressing autologous T‐cell responses independently of each other. In vitro as well as in vivo, Vemurafenib inhibits the generation of human moMDSCs. Thus, Vemurafenib decreases immunosuppression in patients with advanced melanoma, indicating its potential as part of future immunotherapies.

Ageing and myeloid-derived suppressor cells: possible involvement in immunosenescence and age-related disease

“…In mice under tumour conditions, Youn et al (2008) f o u n d t h a t M D S C s u r f a c e m a r k e r s w e r e CD11b ) and multiple myeloma (CD14 + myeloid cells co-expressing CD15) (Feng et al 2013;Schilling et al 2013;Pohla et al 2013;Yang et al 2014;Busch et al 2014). …”

Myeloid-Derived Suppressor Cells Predict Survival of Patients with Advanced Melanoma: Comparison with Regulatory T Cells and NY-ESO-1- or Melan-A–Specific T Cells

“…Various populations of MDSCs with several distinct phenotypes have been described over the last years, with a shared common suppressive function on adaptive and innate immunity (12,13). Circulating MDSCs have been shown to correlate with grading, stage, and tumor burden (14)(15)(16)(17) or with clinical outcome in patients with different types of cancer (18)(19)(20). At present, there are conflicting data on the prognostic significance of circulating MDSCs in melanoma (6,21,22).…”

Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer

“…The first group of cells has been described as CD14 -CD11b + CD33 + CD15 + and the second group as CD14 + human leukocyte antigen-D related (HLA-DR) -/low (13). The absence or low expression of HLA-DR is characteristic in Mo-MDSCs, thus the CD14 + HLA-DR -/low phenotype has been used in studies concerning the identification of Mo-MDSCs in NSCLC (5,14).…”