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12 pages, 2505 KiB

Open AccessFeature PaperArticle

Monocyte Maturation Mediators Upregulate CD83, ICAM-1 and MHC Class 1 Expression on Ewing’s Sarcoma, Enhancing T Cell Cytotoxicity

by Emilie Biele, Sebastian J. Schober, Carolin Prexler, Melanie Thiede, Kristina von Heyking, Hendrik Gassmann, Jennifer Eck, Busheng Xue, Stefan Burdach and Uwe Thiel

Cells 2021, 10(11), 3070; https://doi.org/10.3390/cells10113070 - 08 Nov 2021

Cited by 3 | Viewed by 2030

Abstract

Ewing’s sarcoma (EwS) is a pediatric solid tumor entity with low somatic mutational burden and a low rate of tumor-infiltrating T cells, indicating a low extent of immunogenicity. In EwS, immunogenicity may furthermore be significantly diminished by a predominantly M2 macrophage driven pro-tumorigenic [...] Read more.

Ewing’s sarcoma (EwS) is a pediatric solid tumor entity with low somatic mutational burden and a low rate of tumor-infiltrating T cells, indicating a low extent of immunogenicity. In EwS, immunogenicity may furthermore be significantly diminished by a predominantly M2 macrophage driven pro-tumorigenic tumor microenvironment. In the past, we demonstrated that CHM1³¹⁹-specific TCR-transgenic T cells are able to control EwS growth in a preclinical mouse model as well as in a patient with metastatic disease. However, new adjuvant techniques to induce long lasting and curative CHM1³¹⁹-specific TCR-transgenic T cell-mediated anti-tumor responses are needed. In this work, we sought to identify a technique to improve the cytotoxic effect of CHM1³¹⁹-specific TCR-transgenic T cell by altering the immunogenic cell surface marker expression on EwS cell lines using different cytokines. We demonstrate that TNF, IL-6, IL-1β and PGE₂ cause pro-immunogenic CD83, MHC class I and II as well as ICAM-1 upregulation in EwS cell lines. This observation was associated with significantly improved recognition and killing of the tumor cells by EwS-specific CHM1³¹⁹/HLA-A*02:01-restricted TCR-transgenic T cells. Conclusively, we demonstrate that the induction of an inflammatory signature renders EwS more susceptible to adoptive T cell therapy. TNF, which is upregulated during inflammatory processes, is of particular translational interest as its secretion may be induced in the patients e.g., by irradiation and hyperthermia in the clinical setting. In future clinical protocols, this finding may be important to identify appropriate conditioning regimens as well as point of time for adoptive T cell-based immunotherapy in EwS patients. Full article

(This article belongs to the Special Issue Cell Biology: State-of-the-Art and Perspectives in Germany)

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20 pages, 20773 KiB

Open AccessFeature PaperArticle

RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells

by Eda Demirel, Caroline Arnold, Jaspal Garg, Marius Andreas Jäger, Carsten Sticht, Rui Li, Hanna Kuk, Nina Wettschureck, Markus Hecker and Thomas Korff

Cells 2021, 10(7), 1748; https://doi.org/10.3390/cells10071748 - 11 Jul 2021

Cited by 5 | Viewed by 2905

Abstract

The regulator of G-protein signaling 5 (RGS5) acts as an inhibitor of Gα_q/11 and Gα_i/o activity in vascular smooth muscle cells (VSMCs), which regulate arterial tone and blood pressure. While RGS5 has been described as a crucial determinant regulating the VSMC [...] Read more.

The regulator of G-protein signaling 5 (RGS5) acts as an inhibitor of Gα_q/11 and Gα_i/o activity in vascular smooth muscle cells (VSMCs), which regulate arterial tone and blood pressure. While RGS5 has been described as a crucial determinant regulating the VSMC responses during various vascular remodeling processes, its regulatory features in resting VSMCs and its impact on their phenotype are still under debate and were subject of this study. While Rgs5 shows a variable expression in mouse arteries, neither global nor SMC-specific genetic ablation of Rgs5 affected the baseline blood pressure yet elevated the phosphorylation level of the MAP kinase ERK1/2. Comparable results were obtained with 3D cultured resting VSMCs. In contrast, overexpression of RGS5 in 2D-cultured proliferating VSMCs promoted their resting state as evidenced by microarray-based expression profiling and attenuated the activity of Akt- and MAP kinase-related signaling cascades. Moreover, RGS5 overexpression attenuated ERK1/2 phosphorylation, VSMC proliferation, and migration, which was mimicked by selectively inhibiting Gα_i/o but not Gα_q/11 activity. Collectively, the heterogeneous expression of Rgs5 suggests arterial blood vessel type-specific functions in mouse VSMCs. This comprises inhibition of acute agonist-induced Gα_q/11/calcium release as well as the support of a resting VSMC phenotype with low ERK1/2 activity by suppressing the activity of Gα_i/o. Full article

(This article belongs to the Special Issue Cell Biology: State-of-the-Art and Perspectives in Germany)

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Review

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26 pages, 2149 KiB

Open AccessReview

The Manifold Cellular Functions of von Willebrand Factor

by Angelika Mojzisch and Maria A. Brehm

Cells 2021, 10(9), 2351; https://doi.org/10.3390/cells10092351 - 08 Sep 2021

Cited by 23 | Viewed by 5921

Abstract

The plasma glycoprotein von Willebrand factor (VWF) is exclusively synthesized in endothelial cells (ECs) and megakaryocytes, the precursor cells of platelets. Its primary function lies in hemostasis. However, VWF is much more than just a “fishing hook” for platelets and a transporter for [...] Read more.

The plasma glycoprotein von Willebrand factor (VWF) is exclusively synthesized in endothelial cells (ECs) and megakaryocytes, the precursor cells of platelets. Its primary function lies in hemostasis. However, VWF is much more than just a “fishing hook” for platelets and a transporter for coagulation factor VIII. VWF is a true multitasker when it comes to its many roles in cellular processes. In ECs, VWF coordinates the formation of Weibel–Palade bodies and guides several cargo proteins to these storage organelles, which control the release of hemostatic, inflammatory and angiogenic factors. Leukocytes employ VWF to assist their rolling on, adhesion to and passage through the endothelium. Vascular smooth muscle cell proliferation is supported by VWF, and it regulates angiogenesis. The life cycle of platelets is accompanied by VWF from their budding from megakaryocytes to adhesion, activation and aggregation until the end in apoptosis. Some tumor cells acquire the ability to produce VWF to promote metastasis and hide in a shell of VWF and platelets, and even the maturation of osteoclasts is regulated by VWF. This review summarizes the current knowledge on VWF’s versatile cellular functions and the resulting pathophysiological consequences of their dysregulation. Full article

(This article belongs to the Special Issue Cell Biology: State-of-the-Art and Perspectives in Germany)

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