Myeloid-derived suppressor cells enhance the expression of melanoma-associated antigen A4 in a Lewis lung cancer murine model

Abstract

Abstract. The cancer-testis (CT) family of antigens are expressed in multiple types of malignant neoplasm and are silent in normal tissues, apart from the testis. Immunotherapy targeting CT antigens is a promising therapeutic strategy for treatment of solid tumors. One member of this family, melanoma-associated antigen A4 (MAGE-A4), has been demonstrated to be expressed in melanomas and lung cancer. Patients with tumors expressing the MAGE-A4 antigen exhibit specific cellular and humoral immune responses to the antigen, resulting in a favorable prognosis. Conversely, the expression of MAGE-A4 is associated with poor survival in lung cancer. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells, which are upregulated in the cancer microenvironment. Little is known regarding any potential correlation between the expression of MAGE-A4 antigens and the accumulation of MDSCs. The present study aimed to examine the association between circulating MDSC levels and MAGE-A4 expression in a mouse model of Lewis lung cancer. The expression of MAGE-A4 in tumor cells or tissues was evaluated using western blotting, while the percentage of MDSCs (CD11b + Gr-1 + ) in the blood was detected by flow cytometry. In addition, the suppressive capacity of MDSCs and the effectiveness of MDSC depletion were assessed in C57BL/6 tumor-bearing mice. MDSCs were demonstrated to upregulate MAGE-A4 expression via the phosphosphorylated-signal transducer and activator of transcription 3 705 pathway, while depletion of MDSCs decreased the tumor growth rate, prolonged median survival and enhanced the recognition of MAGE-A4 by CD8 + T cells. These findings indicated that immunotherapeutic strategies involving induction of cytotoxic T lymphocytes that target MAGE-A4, in combination with MDSC depletion, may be an effective approach to immunotherapy for cancer types with high expression of MAGE-A4.

Maelstrom Directs Myeloid-Derived Suppressor Cells to Promote Esophageal Squamous Cell Carcinoma Progression via Activation of the Akt1/RelA/IL8 Signaling Pathway

“…It has been reported that MDSCs supernatant could upregulate another cancer-testis antigen (CTA), MAGE-A4, in lung cancer (34). In accordance with previous studies, we found that MDSC supernatants could significantly upregulate MAEL, activate EMT, and upregulate stemness-associated genes in esophageal cancer cell lines (Fig.…”

“…Shi and colleagues demonstrated that MAGE-A4, a CTA, could be regulated by MDSC supernatants (34), and Sampson and colleagues demonstrated TGFb could upregulate another Figure 6. MAEL could activate the Akt1/RelA signaling pathway to upregulate IL8.…”

Neutrophil, quo vadis?

“…Apparently, numerous recent studies that examine the immunomodulatory role of MDSCs were actually describing immunosuppressive neutrophils. In such studies, authors are often content with using phenotypical evaluation of surface CD11b and/or Ly6G expression, whereas missing, at least in part, the characterization of the suppressive activities of these cells [34][35][36]. Moreover, neutrophil-depletion procedures using anti-Gr1 or anti-Ly6G antibodies are repeatedly presented as MDSC-depleting therapy [37,38].…”

Myeloid‐Derived Suppressor Cells in Cancers and Inflammatory Diseases: Angel or Demon?

“…The name of MDSCs firstly comes from the ability to suppress immune cells via cell‐to‐cell interactions as well as soluble mediators, which have been demonstrated in tumour‐bearing mice models both in vivo and in vitro ; furthermore, in cancer patients, MDSCs were accumulated because myelopoiesis is perturbed instead of generating immunogenic myeloid cells such as dendritic cells, inflammatory macrophages and granulocytes . These cells are distributed systemically, resulting in general immunosuppression.…”