Increased CD14+HLA-DR-/low myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients

Abstract

Accumulating evidence has demonstrated that myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells, play an important role in the subversion, inhibition, and downregulation of the immune response to cancer. However, the characteristics of these cells, particularly clinical relevance, in malignant tumors remain unclear due to a lack of specific markers. In this study, we characterized peripheral CD14(+)HLA-DR(-/low) cells, a new human MDSC subpopulation, in 89 patients with non-small cell lung cancer (NSCLC). As expected, both frequency and absolute number of CD14(+)HLA-DR(-/low) cells were significantly increased in the peripheral blood of NSCLC patients compared with that of the healthy controls and indicated an association with metastasis, response to chemotherapy, and progression-free survival. These cells showed decreased expression of CD16 and CD86 compared with HLA-DR(+) monocytes. Unlike classical monocytes, these populations showed significantly decreased allostimulatory activity and showed the ability to inhibit autologous T cell proliferation and IFN-γ production in a cell-contact-dependent manner. Furthermore, we demonstrated that CD14(+)HLA-DR(-/low) cells expressed the NADPH oxidase component gp91(phox) and generated high level of reactive oxygen species (ROS). Moreover, inactivation of ROS reversed their immunosuppressive capacity on T cell response. These results prove, for the first time, the existence of ROS-producing CD14(+)HLA-DR(-/low) myeloid-derived suppressor cells in NSCLC patients, which mediate tumor immunosuppression and might thus represent a potential target for therapeutic intervention.

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

“…It is well documented that MDSCs and TAMs are associated with poor clinical outcome in patients with solid tumors (22)(23)(24). In human neuroblastoma, tumor-infiltrating inflammatory myeloid cells were analyzed by immunohistochemistry stainings in 133 metastatic tumors and demonstrated independent prognostic values (4).…”

“…However, tumor-induced inflammation limits efficient antitumor immune responses through recruitment of various suppressive immune cell types (15), including myeloidderived suppressor cells (MDSC) and "M2-biased" tumor-associated macrophages (TAM) (16)(17)(18)). These cells demonstrate overlapping phenotypic markers as well as inhibitory mechanisms (19,20) and predict poor clinical outcome in patients with cancer (21)(22)(23)(24).…”

Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells

“…In melanoma, MDSCs are associated with tumor progression, signs of EMT such as decreased E-Cadherin expression and increased migratory capacities of malignant cells 36 . Similarly, MDSCs may contribute to metastatic dissemination of different types of cancer, including NSCLC 43 . Finally, Srivastava’s team demonstrated that when MDSCs were depleted, the size of tumors decreased and cell migration was reduced 44 .…”

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

“…29-34 In patients with non-small cell lung cancer, both frequency and the absolute number of peripheral CD14 + HLA-DR −/low MDSCs subset were significantly increased compared with healthy controls and were associated with metastasis, response to chemotherapy and progression-free survival. 35 In patients with terminal cancer, peripheral blood levels of granulocytic MDSCs correlated with overall survival. Patients with low levels of CD15 + CD16 low cells had significantly longer survival times and patients with high levels of CD15 + CD16 low cells tended to have poor performance status.…”