The immunosuppressive tumor microenvironment represents not only one of the key factors stimulating tumor progression but also a strong obstacle for efficient tumor immunotherapy. Immunosuppression ...was found to be associated with chronic inflammatory mediators including cytokines, chemokines and growth factors produced by cancer and stroma cells. Long-term intensive production of these factors induces the formation of myeloid-derived suppressor cells (MDSCs) representing one of the most important players mediating immunosuppression. Moreover, MDSCs could not only inhibit anti-tumor immune reactions but also directly stimulate tumor growth and metastasis. Therefore, understanding the mechanisms of their generation, expansion, recruitment and activation is required for the development of novel strategies for tumor immunotherapy.
Accumulation of myeloid-derived suppressor cells (MDSC) in melanoma microenvironment is supported by chemokine receptor/chemokine signaling. Although different chemokines were suggested to be ...involved in this process, the role of CCR5 and its ligands is not established. Using a
transgenic mouse melanoma model, we found an accumulation of CCR5
MDSCs in melanoma lesions associated with both increased concentrations of CCR5 ligands and tumor progression. Tumor-infiltrating CCR5
MDSCs displayed higher immunosuppressive activity than their CCR5
counterparts. Upregulation of CCR5 expression on CD11b
Gr1
myeloid cells was induced
by CCR5 ligands and other inflammatory factors. In melanoma patients, CCR5
MDSCs were enriched at the tumor site and correlated with enhanced production of CCR5 ligands. Moreover, they exhibited a stronger immunosuppressive pattern compared with CCR5
MDSCs. Blocking CCR5/CCR5 ligand interactions increased survival of tumor-bearing mice and was associated with reduced migration and immunosuppressive potential of MDSCs in tumor lesions. Our findings define a critical role for CCR5 in recruitment and activation of MDSCs, suggesting a novel strategy for melanoma treatment.
These findings validate the importance of the CCR5/CCR5 ligand axis not only for MDSC recruitment but also for further activation of their immunosuppressive functions in the tumor microenvironment, with potentially broad therapeutic implications, given existing clinically available inhibitors of this axis.
.
Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, leading to the accumulation of myeloid-derived suppressor cells (MDSCs). Using
ret
...transgenic mouse melanoma model, we found a significant migration of MDSCs expressing C-C chemokine receptor (CCR)5 into primary tumors and metastatic lymph nodes, which was correlated with tumor progression. An increased CCR5 expression on MDSCs was associated with elevated concentrations of CCR5 ligands in melanoma microenvironment.
In vitro
experiments showed that the upregulation of CCR5 expression on CD11b
+
Gr1
+
immature myeloid cells was induced by CCR5 ligands, IL-6, GM-CSF, and other inflammatory factors. Furthermore, CCR5
+
MDSCs infiltrating melanoma lesions displayed a stronger immunosuppressive pattern than their CCR5
−
counterparts. Targeting CCR5/CCR5 ligand signaling via a fusion protein mCCR5-Ig, which selectively binds and neutralizes all three CCR5 ligands, increased the survival of tumor-bearing mice. This was associated with a reduced migration and immunosuppressive potential of tumor MDSCs. In melanoma patients, circulating CCR5
+
MDSCs were increased as compared to healthy donors. Like in melanoma-bearing mice, we observed an enrichment of these cells and CCR5 ligands in tumors as compared to the peripheral blood. Our findings define a critical role for CCR5 not only in the recruitment but also in the activation of MDSCs in tumor lesions, suggesting that novel strategies of melanoma treatment could be based on blocking CCR5/CCR5 ligand interactions.
Testing peripheral blood for circulating tumor DNA (ctDNA) offers a minimally invasive opportunity to diagnose, characterize, and monitor the disease in individual cancer patients. ctDNA can reflect ...the actual tumor burden and specific genomic state of disease and thus might serve as a prognostic and predictive biomarker for immune checkpoint inhibitor (ICI) therapy. Recent studies in various cancer entities (e.g., melanoma, non-small cell lung cancer, colon cancer, and urothelial cancer) have shown that sequential ctDNA analyses allow for the identification of responders to ICI therapy, with a significant lead time to imaging. ctDNA assessment may also help distinguish pseudoprogression under ICI therapy from real progression. Developing dynamic changes in ctDNA concentrations as a potential surrogate endpoint of clinical efficacy in patients undergoing adjuvant immunotherapy is ongoing. Besides overall ctDNA burden, further ctDNA characterization can help uncover tumor-specific determinants (e.g., tumor mutational burden and microsatellite instability) of responses or resistance to immunotherapy. In future studies, standardized ctDNA assessments need to be included in interventional clinical trials across cancer entities to demonstrate the clinical utility of ctDNA as a biomarker for personalized cancer immunotherapy.
Calprotectin (S100A8/A9), a heterodimer of the two calcium-binding proteins S100A8 and S100A9, was originally discovered as immunogenic protein expressed and secreted by neutrophils. Subsequently, it ...has emerged as important pro-inflammatory mediator in acute and chronic inflammation. More recently, increased S100A8 and S100A9 levels were also detected in various human cancers, presenting abundant expression in neoplastic tumor cells as well as infiltrating immune cells. Although, many possible functions have been proposed for S100A8/A9, its biological role still remains to be defined. Altogether, its expression and potential cytokine-like function in inflammation and in cancer suggests that S100A8/A9 may play a key role in inflammation-associated cancer.
Chronic inflammation is considered to be one of the hallmarks for tumor initiation and progression. Moreover, a long‐term production and accumulation of inflammatory factors lead to a local and ...systemic immunosuppression associated with cancer progression. However, the correlation between inflammatory mediators, immunosuppressive cells and the clinical outcome of malignant melanoma patients was poorly investigated. In this study, we performed a complex analysis of various inflammatory factors, myeloid‐derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the peripheral blood of patients suffering from malignant melanoma of different stages. We demonstrated that levels of serum IL‐1β, IFN‐γ and CXCL10 were significantly increased in advanced melanoma patients. In addition, these factors were found to be associated with an increased frequency of MDSCs and Tregs as compared to age‐ and gender‐matched healthy donors. Importantly, advanced melanoma patients with signs of progression displayed markedly elevated concentrations of IL‐1β and CXCL10 as compared to patients with stable disease. Moreover, an enrichment of circulating monocytic (Mo)‐MDSCs significantly correlated with a decreased progression free survival of these patients. Our data highlight a complex association between circulating inflammatory mediators, Mo‐MDSCs and the clinical outcome as well as suggest that their levels in patients with advanced melanoma are of important prognostic value allowing the identification of those with high risk of disease progression.
What's new?
Tumor progression can be driven by chronic inflammation that induces local and systemic immunosuppression. In this study of melanoma patients, the authors correlated circulating inflammatory factors, myeloid‐derived suppressor cells (MDSCs), and regulatory T cells (Tregs) with clinical outcome. Patients with advanced melanoma displayed an accumulation of IL‐1b, IFN‐g, CXCL10, monocytic MDSCs (Mo‐MDSCs) and Tregs. Moreover, an increase in IL‐1b, CXCL10 and Mo‐MDSCs correlated with a decreased progression free survival, indicating their important prognostic role.
Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and ...melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) adhesion to the endothelium, intravasation, lung colonization, and postsurgical metastasis. Thus, sustained vascular Notch signaling facilitates metastasis by generating a senescent, pro-inflammatory endothelium. Consequently, treatment with Notch1 or VCAM1-blocking antibodies prevented Notch-driven metastasis, and genetic ablation of EC Notch signaling inhibited peritoneal neutrophil infiltration in an ovarian carcinoma mouse model.
Display omitted
•Tumor ECs frequently have activated Notch1 and this correlates with poor prognosis•Sustained EC Notch1 activity promotes TC migration across the vessel wall•Endothelial Notch1 hyperactivation promotes neutrophil infiltration and metastasis•Neutrophil infiltration and metastasis depend on Notch1-induced VCAM1 expression
Wieland, Rodriguez-Vita et al. reveal that activated Notch1 signaling in endothelial cells (ECs) in tumors and in the pre-metastatic niche induces VCAM1 expression, leading to increased neutrophil infiltration and metastasis. Inhibition of Notch1 or VCAM1 reduces metastasis driven by EC Notch1 in mouse models.
Age matters: Rethinking SLNB's reliability in melanoma mortality prediction Gebhardt, Christoffer
JEADV. Journal of the European Academy of Dermatology and Venereology/Journal of the European Academy of Dermatology and Venereology,
April 2024, 2024-Apr, 20240401, Letnik:
38, Številka:
4
Journal Article
Myeloid-derived suppressor cells in malignant melanoma Umansky, Viktor; Sevko, Alexandra; Gebhardt, Christoffer ...
Journal der Deutschen Dermatologischen Gesellschaft,
November 2014, Letnik:
12, Številka:
11
Journal Article
Recenzirano
Summary
Melanoma is known for its rapid progression, metastasis to distant organs and therapeutic resistance. Despite high melanoma immunogenicity, the results of immunotherapeutic clinical studies ...are mostly unsatisfactory. One explanation is the development of strong immunosuppression mediated by highly immunosuppressive regulatory leukocytes, in particular, myeloid‐derived suppressor cells (MDSCs). These cells were found to be enriched and activated in the melanoma microenvironment, inducing a profound impairment of anti‐tumor immune responses and leading to the tumor progression. Therefore, understanding the mechanisms of MDSC generation, migration to the tumor site and activation as well as their targeting is important for the development of novel strategies for effective melanoma immunotherapy. We suggest that such therapeutic approaches should involve the inhibition of MDSC‐mediated immunosuppressive melanoma microenvironment combined with other immunologic treatments.
PDF
