Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice

Abstract

Cancer immunotherapeutic approaches induce tumor-specific immune responses, in particular CTL responses, in many patients treated. However, such approaches are clinically beneficial to only a few patients. We set out to investigate one possible explanation for the failure of CTLs to eliminate tumors, specifically, the concept that this failure is not dependent on inhibition of T cell function. In a previous study, we found that in mice, myeloidderived suppressor cells (MDSCs) are a source of the free radical peroxynitrite (PNT). Here, we show that pretreatment of mouse and human tumor cells with PNT or with MDSCs inhibits binding of processed peptides to tumor cell-associated MHC, and as a result, tumor cells become resistant to antigen-specific CTLs. This effect was abrogated in MDSCs treated with a PNT inhibitor. In a mouse model of tumor-associated inflammation in which the antitumor effects of antigen-specific CTLs are eradicated by expression of IL-1β in the tumor cells, we determined that therapeutic failure was not caused by more profound suppression of CTLs by IL-1β-expressing tumors than tumors not expressing this proinflammatory cytokine. Rather, therapeutic failure was a result of the presence of PNT. Clinical relevance for these data was suggested by the observation that myeloid cells were the predominant source of PNT in human lung, pancreatic, and breast cancer samples. Our data therefore suggest what we believe to be a novel mechanism of MDSC-mediated tumor cell resistance to CTLs.

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

“…In addition, a mechanism of ROS-mediated cell death has been proposed. 52 Cell-to-cell contact appears to be essential for these mechanisms. 53 However, the mechanisms by which MDSCs promote cancer cell EMT, proliferation, invasion and metastasis are unclear.…”

Characterization of the myeloid-derived suppressor cell subset regulated by NK cells in malignant lymphoma

“…[9][10][11] MDSCs have been intensively studied in spleen 7,11,12 and within a tumor microenvironment. 13,14 In mice, MDSCs are broadly characterized by the expression of CD11b and Gr-1. Using additional markers, these cells can be further divided into three subsets: Gr1 hi or CD11b C Ly6G hi Ly6C low (granulocytic MDSCs) and Gr1 low or CD11b C Ly6G low Ly6C hi (monocytic MDSCs) and Gr1 int or CD11b C Ly6G int Ly6C int MDSCs (non-monocytic and non-granulocytic MDSCs).…”

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.…”