IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy

Weber, Rebekka; Groth, Christopher; Lasser, Samantha; Arkhypov, Ihor; Petrova, Vera; Altevogt, Peter; Utikal, Jochen; Umansky, Viktor

doi:10.1016/j.cellimm.2020.104254

Cited by 198 publications

(148 citation statements)

References 99 publications

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“…In this regard, the accumulation of MDSCs has been shown to depend on two distinct signaling pathways; one is associated with the expansion of immature myeloid cells and the another is associated with their pathological activation (40). In particular, G-CSF is well known as a cytokine associated with the differentiation and trafficking of granulocytic lineage and the generation of PMN-MDSCs (41), whereas IL-6 would promote the systemic accumulation of PMN-MDSCs (42). Our cytokine profile data were consistent with these previous reports.…”

Section: Discussionmentioning

confidence: 99%

CD244⁺ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model

et al. 2021

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Despite the recent development of chemotherapeutic agents, the prognosis of colorectal cancer (CRC) patients with peritoneal dissemination (PD) remains poor. The tumor immune microenvironment (TIME) has drawn attention as a key contributing factor of tumor progression. Of TIME components, myeloid-derived suppressor cells (MDSCs) are considered to play a responsible role in the immunosuppressive characteristics of the TIME. MDSCs are classified into two major subsets: Monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs). Therefore, we hypothesize that MDSCs would play important roles in the PD-relevant TIME and PD progression. To address this hypothesis, we established PD mouse models. As the PD nodules consisted scarcely of immune cells, we focused on the peritoneal cavity, but not PD nodule, to evaluate the PD-relevant TIME. As a result, intraperitoneal PMN-MDSCs were found to be substantially increased in association with PD progression. Based on these results, we phenotypically and functionally verified the usefulness of CD244 for identifying PMN-MDSCs. In addition, the concentrations of interleukin (IL)-6 and granulocyte-colony stimulating factor (G-CSF) were significantly increased in the peritoneal cavity, both of which were produced by the tumors and thought to contribute to the increases in the PMN-MDSCs. In vivo depletion of the PMN-MDSCs by anti-Ly6G monoclonal antibody (mAb) significantly inhibited the PD progression and reverted CD4 + and CD8 + T cells in the peritoneal cavity and the peripheral blood. Collectively, these results suggest that the targeted therapy for PMN-MDSCs would provide not only new therapeutic value but also a novel strategy to synergize with T-cell-based immunotherapy for CRC-derived PD.

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Section: Discussionmentioning

confidence: 99%

CD244⁺ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model

et al. 2021

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“…They are produced during tumor progression and inhibit the antitumor function of T cells and natural killer cells (NK cells). Their abundance is associated with poor prognosis in cancer patients and poor immunotherapy outcomes (Weber et al, 2021). MDSCs have strong immunosuppressive potential and are an important component of the tumor microenvironment (TME).…”

Section: Discussionmentioning

confidence: 99%

The landscape of tumors-infiltrate immune cells in papillary thyroid carcinoma and its prognostic value

Huang

Liu

et al. 2021

PeerJ

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Introduction Thyroid cancer is a very common malignant tumor in the endocrine system, while the incidence of papillary thyroid carcinoma (PTC) throughout the world also shows a trend of increase year by year. In this study, we constructed two models: ICIscore and Riskscore. Combined with these two models, we can make more accurate and reasonable inferences about the prognosis of PTC patients. Methods We selected 481 PTC samples from TCGA and 147 PTC samples from GEO (49 samples in GSE33630, 65 samples in GSE35570 and 33 samples in GSE60542). We performed consistent clustering for them and divided them into three subgroups and screened differentially expressed genes from these three subgroups. Then we divided the differential genes into three subtypes. We also distinguished the up-regulated and down-regulated genes and calculated ICIscore for each PTC sample. ICIscore consists of two parts: (1) the PCAu was calculated from up-regulated genes. (2) the PCAd was calculated from down-regulated genes. The PCAu and PCAd of each sample were the first principal component of the relevant gene. What’s more, we divided the patients into two groups and constructed mRNA prognostic signatures. Additionally we also verified the independent prognostic value of the signature. Results Though ICIscore, we were able to observe the relationship between immune infiltration and prognosis. The result suggests that the activation of the immune system may have both positive and negative consequences. Though Riskscore, we could make more accurate predictions about the prognosis of patients with PTC. Meanwhile, we also generated and validated the ICIscore group and Riskscore group respectively. Conclusion All the research results show that by combining the two models constructed, ICIscore and Riskscore, we can make a more accurate and reasonable inference about the prognosis of patients with clinical PTC patients. This suggests that we can provide more effective and reasonable treatment plan for clinical PTC patients.

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“…The TME plays an important role in tumorigenesis and chemoresistance by close interaction with tumor cells. Furthermore, TME has been shown to be highly immunosuppressive, promoting immune evasion, hence sustaining tumor progression [18][19][20]. Immunotherapy, so far, has not demonstrated substantial clinical improvement as single agent in the treatment of PDAC [5].…”

Section: Plos Onementioning

confidence: 99%

“…The interactions of PDAC tumor cells and different cells within the TME such as CAFs, MDSCs, TAMs, are mediated through GP130/JAK/STAT3 pathway [11,[17][18][19][20]68]. STAT3 inhibition might thus have consequences in shaping TME towards anti-tumor phenotype by acting on both immune and tumor cells [18][19][20]. In combination with chemotherapeutic agents and immunotherapy, it might significantly increase therapeutic efficacy in the treatment of PDAC.…”

Section: Plos Onementioning

confidence: 99%

“…Interactions between different cells within the TME are mediated through signaling molecules such as STAT3 activation via IL-6-type cytokines. For instance, PDAC tumor cells can stimulate immune cells to secrete IL-6-type cytokines, supporting the development of immunosuppressive TAMs and MDSCs as well as the activation of PSCs and CAFs, which in turn induce the secretion of inflammatory cytokines through positive feedback loops [11,[17][18][19][20][21][22]. Thus, STAT3 activation drives immune cells towards immunosuppressive phenotype by inhibiting regulatory T-cells, which in turn sustains tumor immune evasion.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic targeting of STAT3 pathways in pancreatic adenocarcinoma: A systematic review of clinical and preclinical literature

Peisl¹,

Mellenthin²,

Vignot³

et al. 2021

PLoS ONE

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Background/Objectives Pancreatic ductal adenocarcinoma is a highly lethal disease with increasing incidence. Due to high resistance, chemo/radiotherapy has limited success in pancreatic cancer and only marginally prolongs patient survival. Therefore, novel biomarkers and therapeutic targets are needed. In the present review, we performed a comprehensive summary of therapeutic approaches targeting the GP130/JAK/STAT3 pathway. Methods We systematically reviewed the PubMed and Embase databases for preclinical and clinical studies, from inception to October 4, 2020, on drugs targeting the GP130/JAK/STAT3 pathway. Bias assessments and qualitative analyses were performed. Results Twenty-five preclinical and nine clinical trials were included in the review. All preclinical studies reported a favorable outcome in terms of pancreatic ductal adenocarcinoma progression. Futhermore, drugs targeting the GP130/JAK/STAT3 pathway were shown to be efficient chemosensitizers. However, high publication bias was assumed. In the clinical setting, bazedoxifene and itacitinib improved patient outcomes. Conclusion Preclinical studies strongly suggest significant efficacy of drugs targeting GP130/JAK/STAT3 in the treatment of pancreatic ductal adenocarcinoma and that these molecules are effective chemosensitizers. Though only a few trials have shown the efficacy in a clinical setting, the STAT3 pathway remains a promising drug target for future treatment of pancreatic ductal adenocarcinoma and may help overcome chemotherapy resistance.

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IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy

Cited by 198 publications

References 99 publications

CD244⁺ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model

CD244⁺ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model

The landscape of tumors-infiltrate immune cells in papillary thyroid carcinoma and its prognostic value

Therapeutic targeting of STAT3 pathways in pancreatic adenocarcinoma: A systematic review of clinical and preclinical literature

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IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy

Cited by 198 publications

References 99 publications

CD244+ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model

CD244+ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model

The landscape of tumors-infiltrate immune cells in papillary thyroid carcinoma and its prognostic value

Therapeutic targeting of STAT3 pathways in pancreatic adenocarcinoma: A systematic review of clinical and preclinical literature

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Product

Resources

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CD244⁺ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model

CD244⁺ polymorphonuclear myeloid‑derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model