Immunosuppressive Effect Of Myeloid-derived Suppressor Cells Research Articles

Abstract P072: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) foster myeloid-derived suppressor cell-mediated tumor immune evasion in cholangiocarcinoma

Abstract Background and Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is predominantly expressed on immune cells. Although TRAIL biology has garnered considerable interest as a potential anti-cancer strategy, TRAIL agonists have had very limited anti-cancer activity in humans. TRAIL signaling in T cells may also potentially provide an immune checkpoint function as it can inhibit T cell activation and proliferation by interfering with T cell receptor signaling. However, this potential immune checkpoint function of TRAIL has not been examined in cancer biology. Cholangiocarcinoma (CCA), a highly lethal biliary tract cancer, provides a model to examine the potential immune checkpoint function of TRAIL. Methods: Using a syngeneic, orthotopic murine model of CCA (PMID: 29464042), murine CCA cells (SB cells) that express both TRAIL and TRAIL receptor (TR) were implanted into livers of WT and Tr−/− mice. Hence, in this model the host immune cells express TRAIL but not the receptor; therefore, they would be capable of inducing TRAIL-mediated apoptosis in CCA cells but would be resistant to TRAIL-mediated immunosuppression. After 4 weeks of tumor growth, mice were sacrificed, and tumors were characterized using flow cytometry. Results: We observed that Tr−/− mice had a significant reduction in tumor burden compared to WT mice. Moreover, tumor bearing Tr−/− mice had a significant increase in cytotoxic T lymphocytes (CTLs) and enhanced CTL effector function. However, coculture of T cells with SB cells or SB cells deficient in Tr (SB-Tr−/−) did not result in a significant difference in T cell apoptosis or function, implying that TRAIL-TR is not a direct T cell checkpoint. Myeloid derived suppressor cells (MDSCs) were significantly decreased in Tr−/− tumors compared to WT tumors. Furthermore, implantation of SB cells devoid of Trail (SB-Trail−/−) into WT mice resulted in a significant reduction in tumor burden and MDSC infiltration. Coculture of SB cells with MDSCs from Tr−/− mice attenuated MDSC proliferation and immunosuppression compared to WT MDSCs. Moreover, treatment of MDSCs from Tr−/− mice with TRAIL recombinant protein resulted in a reduction in their proliferation and immunosuppressive function compare to MDSCs from WT mice implying that TRAIL-TR fosters MDSC growth and immunosuppressive function. In conclusion, we have demonstrated that Tr−/− mice have a significant reduction in CCA tumor burden and MDSC infiltration. Consequently, Tr−/− mice bearing tumors have enhanced CTL infiltration and function. These data suggest that the TRAIL-TR system mediates tumor immune evasion via MDSCs. Herein, we suggest that TRAIL-TR appears to function as an indirect T cell checkpoint by augmenting the immunosuppressive effects of MDSCs. Citation Format: Emilien Loeuillard, Juan Wang, Jingchun Yang, Haidong Dong, Gregory Gores, Sumera Ilyas. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) foster myeloid-derived suppressor cell-mediated tumor immune evasion in cholangiocarcinoma [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P072.

Connections between Metabolism and Epigenetic Modification in MDSCs.

Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells in the tumor microenvironment (TME). During the differentiation and development of MDSCs from myeloid progenitor cells, their functions are also affected by a series of regulatory factors in the TME, such as metabolic reprogramming, epigenetic modification, and cell signaling pathways. Additionally, there is a crosstalk between these regulatory factors. This review mainly introduces the metabolism (especially glucose metabolism) and significant epigenetic modification of MDSCs in the TME, and briefly introduces the connections between metabolism and epigenetic modification in MDSCs, in order to determine the further impact on the immunosuppressive effect of MDSCs, so as to serve as a more effective target for tumor therapy.

Anti-psoriatic effect of myeloid-derived suppressor cells on imiquimod-induced skin inflammation in mice.

Myeloid-derived suppressor cells (MDSCs) play an important role in controlling the immune response against cancer and in suppression of autoimmunity and allergic inflammation. However, the beneficial effects of MDSCs on the experimental mouse model of psoriasis have not been reported. Therefore, we investigated the anti-psoriatic effect of MDSCs on IMQ-induced skin inflammation in mice and explored the mechanisms involved. Our results showed that administration of MDSCs (1×106 or 2×106 cells) suppressed the development of IMQ-induced skin inflammation in mice as exemplified by a significant reduction in clinical severity scores and was associated with a reduction of histopathological changes, including inflammatory infiltration, epidermal hyperplasia and hyperkeratosis. The immunosuppressive effect of MDSCs (1×106 or 2×106 cells) corresponded to the production of Th1 cytokines (TNF-α, IFN-γ) and Th17 cytokines (IL-17A and IL-23) in the serum and dorsal skin. Administration of MDSCs (1×106 or 2×106 cells) also inhibited splenomegaly. Moreover, an increased percentage of CD4+ CD25+ FoxP3+ regulatory T (Treg) cells and decreased percentage of Th1 and Th17 cells were found in mice treated with MDSCs. Taken together, these results imply that MDSCs have immunomodulatory and immunosuppressive effects on disease progression in a murine model of psoriasis and that MDSCs could be used in preventive or therapeutic strategies for the management of autoimmune inflammatory skin disorders, such as psoriasis.

Abstract 4633: Crosstalk between MDSCs and Th17

Abstract Expansion of myeloid-derived suppressor cells (MDSCs) within the tumor is a known barrier to successful cancer immunotherapy. MDSCs are heterogeneous population of immature myeloid cells with potent immunosuppressive activity. Emerging evidences in the recent years define the role of immunosuppressive activity of MDSCs on different subsets of CD4+ T cells, however the exact effect of MDSCs on inflammatory Th17 cells during tumor progression is not clear. Here we demonstrate the immunosuppressive effect of MDSCs on Th17 cells. We further show that the interaction between MDSCs and Th17 is not unilateral and reveal that Th17 cells can promote the immunosuppressive effect of MDSCs. MDSCs, either isolated from tumor bearing mice or generated in vitro from bone marrow (BM-derived MDSCs), can both suppress IL-17A expression. Our data also demonstrate that IFNg, produced by Th17 cells is essential for the immunosuppressive activity of BM-derived MDSCs on IL-17A expression and further that the IFNgR1-driven signaling is important for Nos2-mediated immunosuppressive effect of BM-derived MDSCs on IL-17A expression. Understanding the molecular mechanism of the interplay between MDSCs and Th17 cells may help to develop more specific targeted therapy for cancer immunotherapy and improve therapeutic efficacy of the existing therapies against cancer. Note: This abstract was not presented at the meeting. Citation Format: Brijendra Singh. Crosstalk between MDSCs and Th17 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4633. doi:10.1158/1538-7445.AM2017-4633

Study on the immunosuppressive activities of myeloid derived suppressor cells in patients suffering from recurrent spontaneous abortion

Objective To investigate the roles of myeloid derived suppressor cells (MDSCs) in the maintenance of maternal immune tolerance and to analyze their associations with recurrent spontaneous abortion (RSA). Methods Peripheral blood samples were collected from sixty subjects including non-pregnant healthy subjects, normal pregnant women and women with recurrent spontaneous abortion aged 25 to 35 years (n=20). Flow cytometry analysis was performed to monitor the changes of MDSCs at the 12th, 24th and 36th weeks of gestational age in three normal pregnant women. The differences with the numbers of MDSCs during the same stage of pregnancy in peripheral blood samples were compared among the three groups by flow cytometry analysis. RT-PCR analysis was used for detection of Arg-1 in women with normal pregnancy and RSA. CD8+ T cells were separated from non-pregnant healthy subjects by using magnetic beads. The immunosuppressive effects of MDSCs, isolated from women with normal pregnancy and RSA, on CD8+ T cells were evaluated by using the 3H thymidine incorporation assay. Results The number of MDSCs increased during normal pregnancy and the differences among different weeks were significant (12th week vs 24th week: P=0.0442, 24th week vs 36th week: P=0.0233, 12th week vs 36th week: P=0.0017). The percentages of MDSCs in peripheral blood of the healthy non-pregnant women were the lowest [(0.937±0.127)%], followed by those in women with RSA [(2.151±0.185)%] and normal pregnant women [(3.777±0.427)%]. There was significant difference with the percentage of MDSCs between women with normal pregnancy and RSA (P=0.0250). Compared with women with normal pregnancy, those with RSA showed significantly decreased levels of Arg-1 (P=0.0474) and suppressed activities of MDSCs against CD8+ T cell proliferation (P=0.0230). Conclusion The MDSCs might play an important role in the maintenance of maternal immune tolerance. Decreased number and inhibited function of MDSCs in the peripheral blood of women with RSA might be responsible for the development of RSA. Key words: Myeloid derived suppressor cell; Maternal immune tolerance; Recurrent spontaneous abortion

Activation of STAT3 promoting immunosuppressive effect on T cells in MDSCs of breast cancer

Objective: To explore the status of STAT3 phosphorylation in myeloid-derived suppressor cells (MDSCs) of breast cancer and its function in the immunosuppressive effect of MDSCs on proliferation and cytokine secretion of T cells. Methods: CCD33 cells were isolated from healthy umbilical cord, blood-derived, peripheral blood mononuclear cells and were co-cultured with breast cancer cell line MDA-MB-231 in vitro using Transwell plates to induce MDSCs. The untreated CD33 cells were used as controls. Idoxuridine (IDO) suppressor expression and STAT3 phosphorylation were examined using Western blot assay. The proliferation and cytokine secretion of T cells, which were co-cultured with MDSCs, were determined by methyl thiazol tetrazolium assay and enzyme-linked immunosorbent assay. 1-MT and JSI-124 were used to investigate the function of IDO and pSTAT3 in MDSC-mediated T cell immunosuppression. Results: The protein levels of IDO and pSTAT3 in MDSCs were significantly upregulated. MDSCs obviously suppressed T-cell proliferation, which was reversed by 1-MT or JSI-124 (P<0.05). MDSCs could promote TGF-β and IL-10 secretions, but could also remarkably inhibit IFN-γ secretion (P<0.05). After incubation with 1-MT or JSI-124, the increase in TGF-β and IL-10, as well as the decrease in IFN-γ, was significantly reversed. Conclusion: The upregulated pSTAT3 induced the IDO increase in MDSCs. JSI-124 can block MDSC-mediated immunosuppressive effect on T cells in breast cancer.

Effects of anti-tumor drugs on myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) play an important immunosuppressive role during the tumor development process.And the progression of many tumors are always accompanied with abnormal accumulation of MDSCs.Moreover,both the accumulation and functions of MDSCs could be affected by complicated factors.Therefore,how to effectively reduce the immunosuppressive effects of MDSCs in oncotherapy has become the focus of scholars.Recent studies show that anti-tumor drugs can affect many biological behaviors of MDSCs. Key words: Myeloid cells; Antineoplastic agents; Immunosuppressive agents; Myeloied derived suppressor cells