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Targeting gamma-glutamyltransferase 1 on myeloid-derived suppressor cells prevents tumor progression caused by G-CSF in neutropenic mouse model

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) are one of the major immunosuppressive cells that accumulate in tumor-bearing hosts. Since MDSCs suppress anti-tumor immunity and promote tumor progression, they are promising targets for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF) is an agent for the treatment of chemotherapy-induced febrile neutropenia in patients with cancer. However, several reports reveal that G-CSF would play crucial immune-related adverse roles in tumor progression through MDSCs. In this study, we showed that MDSCs differentiated in the presence of G-CSF in vitro exhibited the enhanced proliferation and immunosuppressive activity compared with those differentiated without G-CSF. RNA-seq analysis demonstrated that G-CSF enhanced the immunosuppressive function of MDSCs through the upregulation of gamma-glutamyltransferase (GGT) 1. Moreover, in the EL4 lymphoma-bearing neutropenic mouse model, the administration of recombinant G-CSF increased MDSCs and attenuated anti-cancer effect of chemotherapy. We showed that the combination of GGsTop, a GGT inhibitor, with G-CSF could prevent tumor growth caused by G-CSF, without affecting the promoting myelopoiesis by G-CSF. These results suggest that targeting GGT1 on MDSCs can eliminate the effect of G-CSF in promoting tumor growth. GGsTop could be an attractive combination agent when receiving G-CSF treatment for febrile neutropenia in patients with cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE183066 | GEO | 2022/05/13

REPOSITORIES: GEO

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Project description:Tumor growth is associated with a profound alteration of myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). Analyzing the cytokines affecting myelo-monocytic differentiation produced by various experimental tumors, we found that GM-CSF, G-CSF, and IL-6 allowed a rapid generation of MDSCs from precursors present in mouse and human bone marrow (BM). BM-MDSCs induced by GM-CSF+IL-6 possessed the highest tolerogenic activity, as revealed by the ability to impair the priming of IFN- -producing CD8+ T cells upon in vivo adoptive transfer. Moreover, adoptive transfer of syngeneic, GM-CSF+IL-6-conditioned MDSCs to diabetic mice transplanted with allogeneic pancreatic islets resulted in long term acceptance of the allograft and correction of the diabetic status. Cytokines inducing MDSCs acted on a common molecular pathway. Immunoregulatory activity of both tumor-induced and BM-derived MDSCs was entirely dependent on C/EBP transcription factor, a key component of the emergency myelopoiesis triggered by stress and inflammation. Adoptive transfer of tumor antigen-specific CD8+ T lymphocytes resulted in therapy of established tumors only in mice lacking C/EBP in myeloid compartment. These data unveil another link between inflammation and cancer and identify a novel molecular target to control tumor-induced immune suppression. We used gene expression analysis to identify those factors, secreted by tumor-infiltrating MDSC, which could drive emathopoiesis. Moreover we compare gene expression profile of tumor-induced MDSC, obtained from either the spleen and the tumor infiltrate of tumor bearing mice, and in vitro bone marrow-derived MDSC. CD11b+ cells were immunomagnetically enriched from various murine tissue and experimental conditions, and cRNA samples were prepared accordingly to Expression Analysis: Technical Manual. 701021 Rev. 5. Santa Clara, CA, Affymetrix; 2004, and hybridized to the Affymetrix GeneChip MOE430 2.0 array which contains more than 45,000 probe sets, representing more than 34,000 genes. CD11b+ cells obtained from the spleen of healthy BALB/c and C57BL/6 mice were used as reference sample for tumor induced CD11b+ MDSC, enriched from either the spleen and the tumor infiltrate of tumor-bearing mice. Moreover CD11b+ cells enriched from fresh bone marrow were used as reference sample for in vitro bone marrow-differentiated MDSC, obtained with either GM-CSF+IL-6 and GM-CSF+G-CSF 4 days cytokine cocktail treatment.

Project description:Myeloid-derived suppressor cells (MDSCs) potently suppress the anti-tumor immune responses and also orchestrate the tumor microenvironment that favors tumor angiogenesis and metastasis. The immunosuppressive activity of MDSCs has been extensively investigated, however the molecular networks regulating the non-immunological functions of tumor-expanded MDSCs, are largely unknown. In this study, we identified microRNA-494 (miR-494), whose expression was dramatically induced by tumor-derived factors (TDFs), as an essential player, in regulating the non-immunological activity of MDSCs by targeting PTEN and activating the Akt pathway. TGF-beta 1 was found to be a main tumor-derived factor responsible for the up-regulation of miR-494 in MDSCs. Expression of miR-494 not only enhanced CXCR4-mediated MDSC chemotaxis but also altered the intrinsic apoptotic/survival signal by targeting PTEN, thus contributing to the accumulation of MDSCs in tumor tissues. Consequently, down-regulation of PTEN resulted in increased activity of the Akt pathway and the subsequent up-regulation of matrix metalloproteinases (MMPs) for facilitating tumor cell invasion and metastasis. Knock down of miR-494 significantly reversed the activity of MDSCs and inhibited the tumor growth and metastasis of 4T1 murine breast cancer in vivo. Collectively, our findings reveal that TGF-beta 1-induced miR-494 expression in MDSCs plays a critical role in the molecular events governing the accumulation and non-immunological functions of tumor-expanded MDSCs, and might be identified as a potential target in cancer therapy. BALB/c mice (female, 6- to 8-wk-old) were injected subcutaneously in the mammary fat pad with 100,000 4T1 tumor cells. Three weeks later, tumor-bearing animals were used for the indicated studies. Gr-1+ CD11b+ cells were isolated by immunomagnetic selection from the bone marrow of 4T1 tumor-bearing mice (n=3) and tumor-free BALB/c mice (n=3), then the miRNA expression profile were analyzed using miRCURY LNAM-bM-^DM-" microRNA Arrays.

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Targeting gamma-glutamyltransferase 1 on myeloid-derived suppressor cells prevents tumor progression caused by G-CSF in neutropenic mouse model

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