| 1. |
- He, Xingkang, et al.
(författare)
-
Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo
- 2020
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 117:37, s. 22910-22919
-
Tidskriftsartikel (refereegranskat)abstract
- Lymphocyte-based immunotherapy has emerged as a break-through in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.
|
|
| 2. |
- Wu, Jing, et al.
(författare)
-
Interleukin-33 is a Novel Immunosuppressor that Protects Cancer Cells from TIL Killing by a Macrophage-Mediated Shedding Mechanism
- 2021
-
Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 8:21
-
Tidskriftsartikel (refereegranskat)abstract
- Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy.
|
|
| 3. |
- Li, Shuijie, et al.
(författare)
-
Impaired oxygen-sensitive regulation of mitochondrial biogenesis within the von Hippel–Lindau syndrome
- 2022
-
Ingår i: Nature Metabolism. - : Nature Publishing Group. - 2522-5812. ; 4:6, s. 739-758
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondria are the main consumers of oxygen within the cell. How mitochondria sense oxygen levels remains unknown. Here we show an oxygen-sensitive regulation of TFAM, an activator of mitochondrial transcription and replication, whose alteration is linked to tumours arising in the von Hippel–Lindau syndrome. TFAM is hydroxylated by EGLN3 and subsequently bound by the von Hippel–Lindau tumour-suppressor protein, which stabilizes TFAM by preventing mitochondrial proteolysis. Cells lacking wild-type VHL or in which EGLN3 is inactivated have reduced mitochondrial mass. Tumorigenic VHL variants leading to different clinical manifestations fail to bind hydroxylated TFAM. In contrast, cells harbouring the Chuvash polycythaemia VHLR200W mutation, involved in hypoxia-sensing disorders without tumour development, are capable of binding hydroxylated TFAM. Accordingly, VHL-related tumours, such as pheochromocytoma and renal cell carcinoma cells, display low mitochondrial content, suggesting that impaired mitochondrial biogenesis is linked to VHL tumorigenesis. Finally, inhibiting proteolysis by targeting LONP1 increases mitochondrial content in VHL-deficient cells and sensitizes therapy-resistant tumours to sorafenib treatment. Our results offer pharmacological avenues to sensitize therapy-resistant VHL tumours by focusing on the mitochondria.
|
|
| 4. |
- Peng, Hao, et al.
(författare)
-
The effect of silicon on spangle size in hot-dipped 55 wt%Al-Zn coatings
- 2017
-
Ingår i: Surface & Coatings Technology. - : Elsevier. - 0257-8972 .- 1879-3347. ; 327, s. 110-117
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of various silicon levels on spangle size in hot-dipped 55 wt%Al-Zn-xSi (x = 0.5, 1.0, 1.6, 2.0, 4.0, all in wt%) coatings was studied. The results showed that as silicon content was increased from 0.5 to 4.0 wt%, spangle size increased gradually from the minimized range to the normal range. Spangle range transition occurred in silicon content between 1.0 and 1.6 wt%. Correlation between intermetallic species and spangle sizes under various silicon contents was investigated. It was found that in the process of spangle size from the minimized to the normal, intermetallic species of the alloy layer were also subject to a regular change of phase transformation from FeAl3 to T-5 (also refers to alpha-AlFeSi), especially remarkable in the range of silicon content where spangle range transited. Phase evolution of the intermetallic layer in various silicon levels was quantitatively analyzed by thermodynamic modelling using Pandat software package, which provided a deep understanding of how the silicon content affect the formation of intermetallic species and controlled the change of intermetallic layer underneath the overlay. First-principles calculations were performed to evaluate the lattice mismatch between intermetallic species and primary alpha-Al, which gave an interpretation of how the intermetallic species influenced the nucleation behavior of primary alpha-Al during solidification and then controlled the spangle size.
|
|
| 5. |
- Wu, Guangxin, et al.
(författare)
-
Effect of Hot Rolled Substrate of Hydrogen Reduction on Interfacial Reaction Layer of Hot-dip Galvanizing
- 2018
-
Ingår i: Journal of Materials Processing Technology. - : Elsevier. - 0924-0136 .- 1873-4774. ; 259, s. 134-140
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of morphology of substrate on intermetallic layer is studied in this work by combining the hydrogen reduction descaling of hot rolled steel and galvanizing process. The results show that the morphology of iron reduced at different temperatures can be divided into porous and dense iron surface. The interfacial reaction layer on steel strip with porous iron is composed of xi phase and delta phase, and the phase in coating is invariable with the increasing of soaking time. However, the interfacial reaction layer on steel strip with dense iron is considered to be Fe2Al5Znx intermetallic layer. As the time goes up, a columnar xi phase forms on the intermetallic layer of steel strip reduced at 700 degrees C and the Fe-Al intermetallic layer disappears gradually. In addition, the bursting phenomenon of intermetallic layer occurs after dipping for 10s on steel strip reduced at 800 degrees C, and the delta phase forms on the interface between the "outburst" Fe-Al phase and substrate. The possible mechanisms involved in the formation of Fe-Al and Fe-Zn alloys were also discussed.
|
|
| 6. |
- Wu, Guangxin, et al.
(författare)
-
Effect of water pressure and soaking time on the selective oxidation of DP980 advanced high strength steel
- 2018
-
Ingår i: Applied Surface Science. - : Elsevier. - 0169-4332 .- 1873-5584. ; 453, s. 252-262
-
Tidskriftsartikel (refereegranskat)abstract
- Due to the limited heating power in non-oxidation furnace of continuous strip processing facilities of heating stage, selective oxidation with higher oxygen pressure is practically inevitable, which will greatly influence the quality of coating during immersion into the zinc bath. In this paper, the oxidation behaviors of DP980 advanced high strength steel are studied during annealing in a pure H2 atmosphere with controlled water pressure ranging from 0.033 to 0.094 bar (PH2O/PH2) and soaking time from 30 s to 2 h. The oxidation proceeds as a combination of external formation of Mn oxides and internal formation of Mn2SiO4, MnSiO3 and SiO2 from the subsurface of the steel into the matrix. As the water pressure increases from 0.033 to 0.094 bar, it can be seen that the amount of oxide particles and coverage on the surface of the steel seems to decrease initially and increase afterwards. The sequence of oxides determined by oxygen partial pressure was calculated and illustrated using thermodynamics with alloys activity. Oxide growth mechanism during annealing and the effect of water pressure on the amount of oxide particles were also discussed.
|
|
| 7. |
- Wu, Jieyu, et al.
(författare)
-
Disruption of the Clock Component Bmal1 in Mice Promotes Cancer Metastasis through the PAI-1-TGF-beta-myoCAF-Dependent Mechanism
- 2023
-
Ingår i: Advanced Science. - : WILEY. - 2198-3844. ; 10:24
-
Tidskriftsartikel (refereegranskat)abstract
- The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-beta into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-beta signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.
|
|
| 8. |
- Wu, Jieyu
(författare)
-
Targeting stromal components in the tumor microenvironment for cancer therapy
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the tumor microenvironment (TME), different cell components crosstalk with each other through various growth factors, cytokines, chemokines, and enzymes. They offered crucial survival signals for tumor cell proliferation and metastasis. Data presented in this thesis demonstrate approaches to target the stroma of the TME, which provided a novel paradigm for cancer therapy. It involves the conception of overcoming the resistance of conventional therapy, cut-out cancer cell energy support, and interrupting invasive assistance of cancer cells. We specifically focused on these two aspects: first, to resolve antiangiogenic drugs (AAD) resistance in those cancers with a lipid-rich environment or high FGF expression. In addition, to manipulate the brown adipose tissue (BAT) into mega BAT can be an approach in cancer therapy (Paper I-III). Second, we revealed the roles of stromal cells, including the cancerassociated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), in pancreatic ductal adenocarcinoma (PDAC) (Paper IV); and the role of CAFs in the cancer hosts with disturbed circadian rhythm (CR) (Paper V). In Paper I, we revealed the mechanism of AAD drug resistance in tumors surrounded by adipose tissue or lipid-rich environment, for example, colorectal cancer (CRC), PDAC and hepatocellular carcinoma (HCC) in the steatotic liver. Anti-VEGF-based AAD failed to reduce tumor size but triggered vessel regression in tumor tissues, leading to severe hypoxia in the TME. Hypoxia resulted in tumor metabolic reprogramming from glucose-based metabolism to free fatty acids (FFAs)-based metabolism. FFAs provided energy support to tumor cells, leading to accelerate tumor cell proliferation. Inhibition of FFA transporter reversed AAD resistance in anti-tumor effect. Our data suggested a therapeutic approach to reverse the AAD resistance in tumors with a lipid-rich environment. Our previous study revealed the cold exposure and other β3-adrenorecptor stimuli induced the brown adipose tissue (BAT) activation by increasing the non-shivering thermogenesis (NST). The activated BAT decreased blood glucose and impeded glycolysis-based metabolism in cancer cells could suppress tumor growth. In Paper II, we addressed an approach to enlarge BAT into a mega-size BAT (megaBAT) in adult animals. In BAT, the differentiation of certain progenitor cells is controlled by the platelet-derived growth factor receptor α (PDGFRα). Using pharmacological approaches and genetic deletion, we downregulated the PDGFRα in BAT progenitor cells and promoted progenitor cells differentiation into functional brown adipocytes. We found a specific microRNA to target the PDGFRα signaling in vivo. The whole BAT tissue mass was markedly increased after PDGFRα inhibition owing to the increase of brown adipocyte numbers. We found that the obese mice with megaBAT under cold exposure showed improvement in blood glucose level, insulin tolerance, and blood lipid level. Histological analysis showed that the steatotic livers were markedly reversed in obese mice with megaBAT. The megaBAT could become a therapeutic approach to treat cancer and metabolic diseases. We previously reported that fibroblast growth factor 2 (FGF-2) as one of the angiogenic factors contributed to tumor vessel remodeling by recruiting NG2 positive pericytes onto tumor vessels through the PDGFRβ signaling. Therefore, monotherapy with anti-VEGF or anti-PDGFR had become resistant in tumors with high FGF-2 expression. So far, there are no potent anti-FGF drugs available. In Paper III, we found combination therapy with anti-VEGF and anti- PDGFRβ showed superior anti-tumor effects in high FGF-2 tumors. Anti-PDGFRβ treatment suppressed pericyte recruitment, and anti-VEGF precisely targeted tumor vessels. With this study, we provided a new paradigm for resolving AAD resistance by targeting FGF-2 off-target signaling, VEGF and PDGF in cancer therapy. In Paper IV, we identified the CAFs-TAMs crosstalk through the IL-33-ST2-CXCL3-CXCR2 axis in PDAC and triggered cancer cell metastasis. Mouse and human PDAC samples under unbiased genomic-wide profiling analysis and genetic and pharmacological gain/loss-offunction experiments demonstrated a high level of IL-33 expression. IL-33 bound to its receptor ST2 on the TAMs and induced TAMs infiltration. Transcriptomic analysis identified IL-33-ST2 induced high CXCL3 expression, which was produced by TMAs. CXCL3 bound to its receptors CXCR2 on CAFs induced CAFs-myoCAF transition and cell proliferation. CAFs transited to myoCAFs had a high expression of collagen III, which induced the formation of tumor cells and myofibroblast clusters. Tumor cells increased metastasis under this tumormyofibroblasts clusters. Pharmacological targeting of this pathway would provide a potential therapeutic strategy for treating PDAC. Paper V we presented the link between CR disruption and tumor metastasis. We explored CR disruption by using a genetic model of Bmal1 gene knockout (KO) mice. Various types of tumors in Bmal1 KO mice presented high growth speed with an elevated expression of myofibroblast markers. Unbiased genomic-wide profiling using the stromal vascular fraction (SVF) from the tumors of Bmal1 KO mice demonstrated a downregulated expression of the plasminogen activator inhibitor (PAI-1) gene. The BMAL1 protein directly regulated PAI-1 gene transcription. Lacking BMAL1 resulted in low PAI-1 expression, which continuously removed the inhibition of downstream proteins, including tissue plasmin activator (tPA) and urokinase (uPA). The tPA and uPA accumulation transformed plasminogen into plasmin, which converted the latent TGF-β into active form. The active TGF-β contributed to the CAFs transition into myofibroblasts, which induced tumor tissue mass expansion and increased metastasis. Inhibition of TGF-β in tumors with CR disruption or maintenance of CR homeostasis could be a therapeutic approach to tumor therapy. Collectively, the works in this thesis uncover important roles of stromal cellular components in the TME, which lay the ground for the development of novel pharmaceutical approaches in cancer therapy.
|
|
