CD8<sup>+</sup> T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

Tao, Jinglian; Han, Dong; Gao, Shan; Zhang, Wei; Yu, Hong; Liu, Pei; Fu, Rong; Li, Lijuan; Shao, Zhujun

doi:10.1111/jcmm.14825

Cited by 47 publications

(39 citation statements)

References 37 publications

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“… 3 , 6 Our previous research found that MDSCs from MDS have obvious inhibition on CD8 + T cells in vitro . 36 Here, we found that the number of CD8 + T cells decreased, and the number of CD4 + T cells increased in MDS when MDSC expressed a higher TGF-β/TNF-α mRNA ratio. This result further demonstrated that MDSC had an inhibitory effect on CD8 + T cells, and the inhibition of MDSCs might depend on the TGF-β/TNF-α ratio.…”

Section: Discussionmentioning

confidence: 52%

Myeloid-derived suppressor cell cytokine secretion as prognostic factor in myelodysplastic syndromes

Han

Tao

et al. 2020

Innate Immun

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Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that play a critical immunosuppressive role in the tumour micro-environment. Although biological research on MDSCs has made progress, the relationship between the secretion of cytokines by MDSCs and poor prognosis is not clear, and there are no criteria to measure the functional status of MDSCs. Here, we detected the mRNA expression of IL-10, IL-12, TGF-β and TNF-α in MDSCs and the levels of these cytokines in MDSC culture supernatants of patients with myelodysplastic syndromes, and quantified the functional status of MDSCs by IL-10/IL-12 ratio and TGF-β/TNF-α ratio. We found that the ratio of IL-10/IL-12 and TGF-β/TNF-α was significantly higher in higher-risk MDS than in lower-risk MDS and normal control groups. The TGF-β/TNF-α ratio in MDSCs was positively correlated with the percentage of blast cells and was negatively correlated with the percentage of CD3+CD8+ T lymphocytes. Meanwhile, the TGF-β/TNF-α ratio was higher in patients with a lower absolute neutrophil count. It suggested that MDSCs in higher-risk MDS have a stronger immunosuppressive effect and might be related to poor prognosis. Quantifying the functional status of MDSCs with IL-10/IL-12 and TGF-β/TNF-α ratio might help to evaluate the balance of cellular immunity of MDSCs in MDS.

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Section: Discussionmentioning

confidence: 52%

Myeloid-derived suppressor cell cytokine secretion as prognostic factor in myelodysplastic syndromes

Han

Tao

et al. 2020

Innate Immun

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“…Supporting this notion, it has been reported that IL-17 triggers the recruitment of CD11b + Gr-1 + MDSCs to mediate CD8 + T cell exhaustion in hepatitis B virus infection 44 and the CD11b + Gr-1 + MDSCs have been suggested to promote CD8 + T cell exhaustion through Tim-3/Galectin-9 pathway in myelodysplastic syndromes. 45 Given the role of IL-17RA signaling in CD8 + T cell survival and dysfunction in parasite infection; however, we do not rule out the direct effect of IL-17 on CD8 + TIL exhaustion. 46 Further studies are needed to elucidate the detailed cellular and molecular mechanisms by which IL-17-producing cells exert CD8 + T cell exhaustion.…”

Section: Discussionmentioning

confidence: 85%

Type 17 immunity promotes the exhaustion of CD8⁺ T cells in cancer

Kim

Kuen

Koh

et al. 2021

J Immunother Cancer

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BackgroundMultiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) remain unclear.MethodsTo determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8+ TILs in Il17a−/− mice, Il17aCreR26DTA mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4+ T cells or CD11b+Gr-1hi myeloid cells in vivo, respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset.ResultsDepletion of CD4+ T cells promotes the exhaustion of CD8+ T cells with a concomitant increase in IL-17-producing CD8+ T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8+ T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103+KLRG1−IL-7Rαhi tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1hiTim3+TOX+ terminally exhausted CD8+ T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8+ T cells and also delays tumor growth in vivo. Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8+ T cell exhaustion signature gene sets in multiple cancers.ConclusionIL-17-producing cells promote terminal exhaustion of CD8+ T cells and tumor progression in vivo, which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8+ T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.

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“…In the TME, TIM3 mainly mediates T cell apoptosis and participates in tumor immunosuppression, and occurrence and development of tumors. TIM3 has four types of ligands, including carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), high-mobility group box 1 (HMGB1), phosphatidylserine (PtdSer), and Galectin-9 (Gal-9) ( Tao et al, 2020 ). Gal-9 was the first ligand to be identified, and its binding with TIM3 inhibits the T cell immune response and induces tumorigenesis.Tumor growth rates were significantly increased in TIM3-overexpressing EL4 mice ( Nakajima et al, 2019 ).…”

Section: Survey Methodologymentioning

confidence: 99%

The regulation of immune checkpoints by the hypoxic tumor microenvironment

et al. 2021

PeerJ

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The tumor microenvironment (TME) influences the occurrence and progression of tumors, and hypoxia is an important characteristic of the TME. The expression of programmed death 1 (PD1)/programmed death-ligand 1 (PDL1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and other immune checkpoints in hypoxic malignant tumors is often significantly increased, and is associated with poor prognosis. The application of immune checkpoint inhibitors (ICIs) for treating lung cancer, urothelial carcinoma, and gynecological tumors has achieved encouraging efficacy; however, the rate of efficacy of ICI single-drug treatment is only about 20%. In the present review, we discuss the possible mechanisms by which the hypoxic TME regulates immune checkpoints. By activating hypoxia-inducible factor-1α (HIF-1α), regulating the adenosine (Ado)-A2aR pathway, regulating the glycolytic pathway, and driving epithelial-mesenchymal transition (EMT) and other biological pathways, hypoxia regulates the expression levels of CTLA4, PD1, PDL1, CD47, lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM3), and other immune checkpoints, which interfere with the immune effector cell anti-tumor response and provide convenient conditions for tumors to escape immune surveillance. The combination of HIF-1α inhibitors, Ado-inhibiting tumor immune microenvironment regulatory drugs, and other drugs with ICIs has good efficacy in both preclinical studies and phase I-II clinical studies. Exploring the effects of TME hypoxia on the expression of immune checkpoints and the function of infiltrating immune cells has greatly clarified the relationship between the hypoxic TME and immune escape, which is of great significance for the development of new drugs and the search for predictive markers of the efficacy of immunotherapy for treating malignant tumors. In the future, combination therapy with hypoxia pathway inhibitors and ICIs may be an effective anti-tumor treatment strategy.

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CD8⁺ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

Cited by 47 publications

References 37 publications

Myeloid-derived suppressor cell cytokine secretion as prognostic factor in myelodysplastic syndromes

Myeloid-derived suppressor cell cytokine secretion as prognostic factor in myelodysplastic syndromes

Type 17 immunity promotes the exhaustion of CD8⁺ T cells in cancer

The regulation of immune checkpoints by the hypoxic tumor microenvironment

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CD8+ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

Cited by 47 publications

References 37 publications

Myeloid-derived suppressor cell cytokine secretion as prognostic factor in myelodysplastic syndromes

Myeloid-derived suppressor cell cytokine secretion as prognostic factor in myelodysplastic syndromes

Type 17 immunity promotes the exhaustion of CD8+ T cells in cancer

The regulation of immune checkpoints by the hypoxic tumor microenvironment

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CD8⁺ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

Type 17 immunity promotes the exhaustion of CD8⁺ T cells in cancer