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Toll-like receptor 2 ligand and interferon-? suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells.

ABSTRACT: CD11b⁺Gr1⁺ myeloid-derived suppressor cells (MDSCs) suppress activation/proliferation of cytotoxic T cells, thereby hindering cancer immunotherapy. MDSCs are increased after adjuvant therapy with toll-like receptor (TLR) 2 ligands, such as Pam2CSK4, in tumor-bearing mice. However, it remains unknown if the activation of TLR2 in MDSCs affects their function and the therapeutic efficacy of TLR2 ligand. Here, we show that TLR2 signaling in CD11b⁺Ly6G^-Ly6C^high monocytic MDSCs (M-MDSCs), but not CD11b⁺Ly6G⁺Ly6C^low granulocytic MDSCs (G-MDSCs), enhances their immunosuppressive activity, thereby limiting anti-tumor T cell responses induced by TLR2-activated dendritic cells (DCs). iNOS induction was critical for Pam2CSK4-enhanced T cell suppression by M-MDSCs. iNOS was expressed in M-MDSC-derived macrophages, but not undifferentiated M-MDSCs, in cocultures with CD8⁺ T cells, CD11c⁺ DCs, antigen peptide and Pam2CSK4. Pam2CSK4 increased the differentiation frequency of M-MDSCs to macrophages, and iNOS expression required interferon-? (IFN-?) production by CD8⁺ T cells that had been transiently stimulated by M-MDSC-derived macrophages in an antigen/TLR2-dependent manner. Although Pam2CSK4 triggered DC maturation and tumor regression via induction of tumor antigen-specific cytotoxic T lymphocyte (CTL) responses in tumor-bearing mice, Pam2CSK4 plus antigen increased the frequency of iNOS⁺ macrophages in the tumor. Treatment with iNOS inhibitor enhanced the therapeutic efficacy of Pam2CSK4. Hence, the results suggest that TLR2 ligand and T cell-derived IFN-? enhance M-MDSC-mediated immunosuppression, which may negatively regulate anti-tumor CTL response.

SUBMITTER: Shime H

PROVIDER: S-EPMC5739553 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Toll-like receptor 2 ligand and interferon-γ suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells.

Shime Hiroaki H Maruyama Akira A Yoshida Sumito S Takeda Yohei Y Matsumoto Misako M Seya Tsukasa T

Oncoimmunology 20170921 1

CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) suppress activation/proliferation of cytotoxic T cells, thereby hindering cancer immunotherapy. MDSCs are increased after adjuvant therapy with toll-like receptor (TLR) 2 ligands, such as Pam2CSK4, in tumor-bearing mice. However, it remains unknown if the activation of TLR2 in MDSCs affects their function and the therapeutic efficacy of TLR2 ligand. Here, we show that TLR2 signaling in CD11b+Ly6G-Ly6C ...[more]

PMID: 29296526

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Project description:Coronavirus disease 2019 (COVID-19) caused by SARS Coronavirus 2 (CoV2) is associated with massive immune activation and hyperinflammatory response. Acute and severe CoV2 infection is characterized by the expansion of myeloid derived suppressor cells (MDSC) because of cytokine storm, these MDSC suppress T cell functions. However, the presence of MDSC and its effect on CoV2 antigen specific T cell responses in individuals long after first detection of CoV2 and recovery from infection has not been studied. We and others have previously shown that CD11b+CD33+CD14+HLA-DR-/lo monocytic MDSC (M-MDSC) are present in individuals with clinical recovery from viral infection. In this study, we compared the frequency, functional and transcriptional signatures of M-MDSC isolated from CoV2 infected individuals after 5-months of the first detection of the virus (CoV2+) and who were not infected with CoV2 (CoV2-). Compared to CoV2- individuals, M-MDSC were present in CoV2+ individuals at a higher frequency, the level of M-MDSC correlated with the quantity of IL-6 in the plasma. Compared to CoV2-, increased frequency of PD1+, CD57+ and CX3CR1+ T effector memory (TEM) cell subsets was also present in CoV2+ individuals, but these did not correlate with M-MDSC levels. Furthermore, depleting M-MDSC from peripheral blood mononuclear cells (PBMC) increased T cell cytokine production when cultured with the peptide pools of immune dominant spike glycoprotein (S), membrane (M), and nucleocapsid (N) antigens of CoV2. M-MDSC suppressed CoV2 S- antigen-specific T cell in ROS, Arginase, and TGFβ dependent manner. Our gene expression, RNA-seq and pathway analysis studies further confirm that M-MDSC isolated from CoV2+ individuals are enriched in pathways that regulate both innate and adaptive immune responses, but the genes regulating these functions (HLA-DQA1, HLA-DQB1, HLA-B, NLRP3, IL1β, CXCL2, CXCL1) remained downregulated in M-MDSC isolated from CoV2+ individuals. These results demonstrate that M-MDSC suppresses recall responses to CoV2 antigens long after recovery from infection. Our findings suggest M-MDSC as novel regulators of CoV2 specific T cell responses, and should be considered as target to augment responses to vaccine.

Project description:The goal of this study was to determine changes in the expression of genes in monoctic myleoid derived suppressor cells (M-MDSC) as a result of SARS CoV2 infection. The study aimed to investigate if M-MDSC are functionally active and inhibit T cell function in response to SARS CoV2 antigens 5 months after first detection of the virus. Methods: Peripheral blood mononuclear cells (PBMC) were collected from CoV2 (-) and CoV2 (+) donors (N=5 each group). M-MDSC were isolated by flow cytometry, and RNA extracted for RNA-seq studies. Filtering low quality reads and removal of the 3’ adapter sequences were performed using the Trim Galore tool. Reads were mapped to the latest version of the human genome (build hg38) using HISAT2. Mapped reads were counted against the human GENCODE annotation (v37) using HT-Seq. The EdgeR library in the R computing environment was used for quality control of the RNA-Seq data, and ComBat-seq method for correction of batch effects. Differential gene expression analysis was conducted using EdgeR. Pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8. Results: An average of 34 million reads per sample were acquired and mapped to the human genome (build hg38). After applying filtering criteria, 9,217 human genes were identified with the HISAT2 and HTSeq workflow. Differential expression analysis was performed between CoV2 (+) and CoV2 (-) samples using EdgeR. A total of 188 differentially expressed genes (DEGs) were identified with nominal p-value <0.05; of which 63 were up- and 125 downregulated in CoV2 (+) samples. A total of 12 DEGs were identified with false discovery rate corrected p-value <0.05, of which 2 were up- and 10 downregulated. Pathway enrichment analysis identified pathways involved in immune response and innate immune signaling. Conclusion: The study demonstrated that CoV2 infection modulated the expression of genes involved in immune response and innate immune signaling. Most of the genes remained downregulated even after 5 months of first detection of SARS CoV2.

Project description:BACKGROUND:Myeloid-derived suppressor cells (MDSCs) are potent suppressors of immune function and may play a key role in the development and progression of metastatic cancers. Aerobic exercise has been shown to have anticancer effects, yet the mechanisms behind this protection are largely unknown. Therefore, we examined the effects of physical activity on MDSC accumulation and function. METHODS:Female BALB/c mice were assigned to one of two primary groups: sedentary tumor (SED+TUM) or wheel run tumor (WR+TUM). After 6 weeks of voluntary wheel running, all animals were randomly subdivided into 4 different timepoint groups; 16, 20, 24, and 28 days post-tumor injection. All mice were inoculated with 4T1 mammary carcinoma cells in the mammary fat pad and WR groups continued to run for the specified time post-injection. Spleen, blood, and tumor samples were analyzed using flow cytometry to assess proportions of MDSCs. RESULTS:Cells expressing MDSC biomarkers were detected in the spleen, blood, and tumor beginning at d16. However, since there was no evidence of immunosuppressive function until d28, we refer to them as immature myeloid cells (IMCs). Compared to SED+TUM, levels of IMCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33.0 ± 5.2%; 23.1 ± 10.2% of total cells, respectively) and day 20 (33.9 ± 8.1%; 24.3 ± 5.1% of total cells, respectively). Additionally, there were fewer circulating IMCs in WR+TUM at day 16 and MDSC levels were significantly lower (p < 0.05) in the tumor at day 28 in WR+TUM. Additionally, a non-significant 62% and 26% reduction in metastatic lung nodules was observed at days 24 and 28, respectively. At day 28, MDSCs harvested from SED+TUM significantly suppressed CD3+CD4+ T cell proliferation (3.2 ± 1.3 proliferation index) while proliferation in WR+TUM MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls. CONCLUSIONS:These findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies.

Dataset Information

Toll-like receptor 2 ligand and interferon-? suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells.

Publications

Toll-like receptor 2 ligand and interferon-γ suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells.

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