bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒06‒11
sixteen papers selected by
Peio Azcoaga
Biodonostia HRI
  1. The immunomodulatory role of exosomal microRNA networks in the crosstalk between tumor-associated myeloid-derived suppressor cells and tumor cells.
  2. Modulation of T cell function and survival by the tumor microenvironment.
  3. Cancer immune exclusion: breaking the barricade for a successful immunotherapy.
  4. Advances in landscape and related therapeutic targets of the prostate tumor microenvironment.
  5. Sophisticated genetically engineered macrophages, CAR-Macs, in hitting the bull's eye for solid cancer immunotherapy approaches.
  6. Crosstalk between arginine, glutamine, and the branched chain amino acid metabolism in the tumor microenvironment.
  7. Fumarate disarms CD8+ T cells against cancer.
  8. Exosomes-regulated lipid metabolism in tumorigenesis and cancer progression.
  9. Epigenetic regulation and therapeutic targets in the tumor microenvironment.
  10. SIRPα blockade improves the antitumor immunity of radiotherapy in colorectal cancer.
  11. Multiomics technologies for comprehensive tumor microenvironment analysis in triple-negative breast cancer under neoadjuvant chemotherapy.
  12. Robust IL-2-dependent antitumor immunotherapy requires targeting the high-affinity IL-2R on tumor-specific CD8+ T cells.
  13. Review immune response of targeting CD39 in cancer.
  14. Immuno-oncology-microbiome axis of gastrointestinal malignancy.
  15. The role of tumor-infiltrating lymphocytes in triple-negative breast cancer and the research progress of adoptive cell therapy.
  16. Combination of CAR‑T cell therapy and radiotherapy: Opportunities and challenges in solid tumors (Review).
  1. Int Immunopharmacol. 2023 Jun 03. pii: S1567-5769(23)00589-1. [Epub ahead of print]120 110267
    The immunomodulatory role of exosomal microRNA networks in the crosstalk between tumor-associated myeloid-derived suppressor cells and tumor cells.
    Elham Shokati, Elahe Safari.
      Myeloid-derived suppressor cells (MDSCs) are considered a heterogeneous group of immature myeloid cells engaging in aggressive tumor progression and metastasis in the tumor microenvironment (TME) of patients diagnosed with cancer, through downregulation of anti-tumor immune responses. Exosomes are small vesicles carrying specific cargos, including proteins, lipids, and MicroRNA (miRNAs). Such exosomal miRNAs delivered by MDSCs and tumor cells are short noncoding RNAs mediating some of the immunosuppressive characteristics of MDSCs in the TME. However, when it comes to cancer diseases, how these miRNAs interact with MDSCs and encourage MDSCs differentiation and function need further investigations. In this review, we discuss MDSC-derived exosomal miRNAs and those derived from tumor cells (TDE) could modulate anti-tumor immunity and regulate the interaction between tumor cells and MDSCs in the TME. Afterward, we focus on dividing miRNAs, as an important substance interacting with MDSCs and tumor cells in the TME, into those have an immunosuppressive or stimulating effect not only on MDSCs expansion, differentiation, and suppressive function but also on tumor evasion.
    Keywords:  Exosomes; Immunosuppressive function; MicroRNA; Myeloid-derived suppressor cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2023.110267
  2. Front Cell Dev Biol. 2023 ;11 1191774
    Modulation of T cell function and survival by the tumor microenvironment.
    Nikita Mani, Dathan Andrews, Rebecca C Obeng.
      Cancer immunotherapy is shifting paradigms in cancer care. T cells are an indispensable component of an effective antitumor immunity and durable clinical responses. However, the complexity of the tumor microenvironment (TME), which consists of a wide range of cells that exert positive and negative effects on T cell function and survival, makes achieving robust and durable T cell responses difficult. Additionally, tumor biology, structural and architectural features, intratumoral nutrients and soluble factors, and metabolism impact the quality of the T cell response. We discuss the factors and interactions that modulate T cell function and survive in the TME that affect the overall quality of the antitumor immune response.
    Keywords:  T cell function; immune checkpoint; immunosuppression; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2023.1191774
  3. Front Oncol. 2023 ;13 1135456
    Cancer immune exclusion: breaking the barricade for a successful immunotherapy.
    Sofia Bruni, María Florencia Mercogliano, Florencia Luciana Mauro, Rosalia Inés Cordo Russo, Roxana Schillaci.
      Immunotherapy has changed the course of cancer treatment. The initial steps were made through tumor-specific antibodies that guided the setup of an antitumor immune response. A new and successful generation of antibodies are designed to target immune checkpoint molecules aimed to reinvigorate the antitumor immune response. The cellular counterpart is the adoptive cell therapy, where specific immune cells are expanded or engineered to target cancer cells. In all cases, the key for achieving positive clinical resolutions rests upon the access of immune cells to the tumor. In this review, we focus on how the tumor microenvironment architecture, including stromal cells, immunosuppressive cells and extracellular matrix, protects tumor cells from an immune attack leading to immunotherapy resistance, and on the available strategies to tackle immune evasion.
    Keywords:  extracellular matrix; immune exclusion; myeloid cells; physical barrier; tumor infiltrating lymphocytes (TILs); tumor microenvironment; tumor-associated macrophage (TAMs); tumor-associated vasculature
    DOI:  https://doi.org/10.3389/fonc.2023.1135456
  4. Acta Biochim Biophys Sin (Shanghai). 2023 Jun 09.
    Advances in landscape and related therapeutic targets of the prostate tumor microenvironment.
    Duocai Li, Weidong Xu, Yifan Chang, Yutian Xiao, Yundong He, Shancheng Ren.
      The distinct tumor microenvironment (TME) of prostate cancer (PCa), which promotes tumor proliferation and progression, consists of various stromal cells, immune cells, and a dense extracellular matrix (ECM). The understanding of the prostate TME extends to tertiary lymphoid structures (TLSs) and metastasis niches to provide a more concise comprehension of tumor metastasis. These constituents collectively structure the hallmarks of the pro-tumor TME, including immunosuppressive, acidic, and hypoxic niches, neuronal innervation, and metabolic rewiring. In combination with the knowledge of the tumor microenvironment and the advancement of emerging therapeutic technologies, several therapeutic strategies have been developed, and some of them have been tested in clinical trials. This review elaborates on PCa TME components, summarizes various TME-targeted therapies, and provides insights into PCa carcinogenesis, progression, and therapeutic strategies.
    Keywords:  hallmarks; immunotherapy; prostate cancer; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3724/abbs.2023092
  5. Clin Exp Med. 2023 Jun 06.
    Sophisticated genetically engineered macrophages, CAR-Macs, in hitting the bull's eye for solid cancer immunotherapy approaches.
    Nese Unver.
      Studies have begun to employ macrophages engineered with chimeric antigen receptor (CAR-Macs) against solid tumors since they can enter solid tumor tissue and interact with approximately all cellular components in the tumor microenvironment. The chimeric antigen receptor (CAR) has emerged as an appealing strategy for improving immune cells' ability to detect cancer. Tumor-associated macrophages (TAMs) generated with CAR designs exhibit appropriate potency based on their capacity to enter solid tumors and communicate through the inhibitory tumor microenvironment. CAR-Macs technology is a new therapeutic method for attacking cancer cells by switching pro-tumoral M2 macrophages to anti-tumoral M1 macrophages, enhancing macrophage phagocytosis, or increasing antigen presentation activity. CAR-Macs may have a prevailing impact on surrounding immune cells, indicating that they retain anti-tumor activity in the presence of human M2 macrophages, demonstrating their use in CAR technology. Understanding the biology of TAM and targeting novel domains for the advanced CAR-Macrophage platform, it will be feasible to add a new dimension to immunotherapy techniques used exclusively in solid malignancies. This review describes how CAR-Macs technologies modulate CAR-Macrophage production, potential target biomarkers on these platforms, their role in immunotherapeutic approaches, and tumor microenvironment.
    Keywords:  CAR-Macs; Immunotherapy; M2 macrophage; Macrophage
    DOI:  https://doi.org/10.1007/s10238-023-01106-0
  6. Front Oncol. 2023 ;13 1186539
    Crosstalk between arginine, glutamine, and the branched chain amino acid metabolism in the tumor microenvironment.
    Tanner J Wetzel, Sheila C Erfan, Lucas D Figueroa, Leighton M Wheeler, Elitsa A Ananieva.
      Arginine, glutamine, and the branched chain amino acids (BCAAs) are a focus of increased interest in the field of oncology due to their importance in the metabolic reprogramming of cancer cells. In the tumor microenvironment (TME), these amino acids serve to support the elevated biosynthetic and energy demands of cancer cells, while simultaneously maintaining the growth, homeostasis, and effector function of tumor-infiltrating immune cells. To escape immune destruction, cancer cells utilize a variety of mechanisms to suppress the cytotoxic activity of effector T cells, facilitating T cell exhaustion. One such mechanism is the ability of cancer cells to overexpress metabolic enzymes specializing in the catabolism of arginine, glutamine, and the BCAAs in the TME. The action of such enzymes supplies cancer cells with metabolic intermediates that feed into the TCA cycle, supporting energy generation, or providing precursors for purine, pyrimidine, and polyamine biosynthesis. Armed with substantial metabolic flexibility, cancer cells redirect amino acids from the TME for their own advantage and growth, while leaving the local infiltrating effector T cells deprived of essential nutrients. This review addresses the metabolic pressure that cancer cells exert over immune cells in the TME by up-regulating amino acid metabolism, while discussing opportunities for targeting amino acid metabolism for therapeutic intervention. Special emphasis is given to the crosstalk between arginine, glutamine, and BCAA metabolism in affording cancer cells with metabolic dominance in the TME.
    Keywords:  TME; arginine; glutamine; isoleucine; leucine; metabolism; valine
    DOI:  https://doi.org/10.3389/fonc.2023.1186539
  7. Cell Metab. 2023 Jun 06. pii: S1550-4131(23)00182-1. [Epub ahead of print]35(6): 907-909
    Fumarate disarms CD8+ T cells against cancer.
    Luigi Nezi, Teresa Manzo.
      The composition of nutrients in the tumor microenvironment is a key determinant of anti-tumor CD8+ T cell response. In this issue of Cell Metabolism, Jiang and colleagues unveil that tumor-derived fumarate dampens TCR signaling in CD8+ T cells, resulting in defective activation, loss of effector functions, and associated failure of tumor control.
    DOI:  https://doi.org/10.1016/j.cmet.2023.05.005
  8. Cytokine Growth Factor Rev. 2023 May 24. pii: S1359-6101(23)00022-9. [Epub ahead of print]
    Exosomes-regulated lipid metabolism in tumorigenesis and cancer progression.
    Leiguang Ye, Yingpu Li, Sifan Zhang, Jinsong Wang, Bo Lei.
      Increasing evidence highlights the role of lipid metabolism in tumorigenesis and tumor progression. Targeting the processes of lipid metabolism, including lipogenesis, lipid uptake, fatty acid oxidation, and lipolysis, is an optimal strategy for anti-cancer therapy. Beyond cell-cell membrane surface interaction, exosomes are pivotal factors that transduce intercellular signals in the tumor microenvironment (TME). Most research focuses on the role of lipid metabolism in regulating exosome biogenesis and extracellular matrix (ECM) remodeling. The mechanisms of exosome and ECM-mediated reprogramming of lipid metabolism are currently unclear. We summarize several mechanisms associated with the regulation of lipid metabolism in cancer, including transport of exosomal carriers and membrane receptors, activation of the PI3K pathway, ECM ligand-receptor interactions, and mechanical stimulation. This review aims to highlight the significance of these intercellular factors in TME and to deepen the understanding of the functions of exosomes and ECM in the regulation of lipid metabolism.
    Keywords:  CD36; ECM; Exosome; Lipid metabolism; Mechanotransduction; TME
    DOI:  https://doi.org/10.1016/j.cytogfr.2023.05.002
  9. Mol Biomed. 2023 Jun 05. 4(1): 17
    Epigenetic regulation and therapeutic targets in the tumor microenvironment.
    Zhuojun Xie, Zirui Zhou, Shuxian Yang, Shiwen Zhang, Bin Shao.
      The tumor microenvironment (TME) is crucial to neoplastic processes, fostering proliferation, angiogenesis and metastasis. Epigenetic regulations, primarily including DNA and RNA methylation, histone modification and non-coding RNA, have been generally recognized as an essential feature of tumor malignancy, exceedingly contributing to the dysregulation of the core gene expression in neoplastic cells, bringing about the evasion of immunosurveillance by influencing the immune cells in TME. Recently, compelling evidence have highlighted that clinical therapeutic approaches based on epigenetic machinery modulate carcinogenesis through targeting TME components, including normalizing cells' phenotype, suppressing cells' neovascularization and repressing the immunosuppressive components in TME. Therefore, TME components have been nominated as a promising target for epigenetic drugs in clinical cancer management. This review focuses on the mechanisms of epigenetic modifications occurring to the pivotal TME components including the stroma, immune and myeloid cells in various tumors reported in the last five years, concludes the tight correlation between TME reprogramming and tumor progression and immunosuppression, summarizes the current advances in cancer clinical treatments and potential therapeutic targets with reference to epigenetic drugs. Finally, we summarize some of the restrictions in the field of cancer research at the moment, further discuss several interesting epigenetic gene targets with potential strategies to boost antitumor immunity.
    Keywords:  Epigenetic drugs; Epigenetics; Immune checkpoint inhibitors; Tumour microenvironment
    DOI:  https://doi.org/10.1186/s43556-023-00126-2
  10. Cell Death Discov. 2023 Jun 09. 9(1): 180
    SIRPα blockade improves the antitumor immunity of radiotherapy in colorectal cancer.
    Kai Ji, Yuhan Zhang, Shengpeng Jiang, Lin Sun, Baozhong Zhang, Dongzhi Hu, Jun Wang, Lujun Zhao, Ping Wang, Zhen Tao.
      High-dose hypofractionated radiotherapy (HRT) is an important anticancer treatment modality that activates antitumor host immune responses. However, HRT for oligometastases of colorectal cancer (CRC) has shown frustrating results in the clinic. As part of immune evasion, myeloid cells express signal regulatory protein α (SIRPα) to inhibit phagocytosis by phagocytes in the tumor microenvironment (TME). We postulated that SIRPα blockade enhances HRT by alleviating the inhibitory action of SIRPα on phagocytes. We demonstrated that SIRPα on myeloid cells was upregulated in the TME after HRT. When SIRPα blockade was administered with HRT, we observed superior antitumor responses compared with anti-SIRPα or HRT alone. When anti-SIRPα was administered to local HRT, the TME could become a tumoricidal niche that was heavily infiltrated by activated CD8+ T cells, but with limited myeloid-derived suppressor cells and tumor-associated macrophages. While CD8+ T cells were required for the effectiveness of the anti-SIRPα + HRT combination. The triple therapy with anti-SIRPα + HRT + anti-PD-1 had superior antitumor responses compared with the combination of any two therapies and established a strong and long-lasting adaptive immunological memory. Collectively, SIRPα blockade provides a novel way to overcome HRT resistance in oligometastatic CRC patients. Our results herein provide a valuable cancer treatment strategy that has the potential to be translated into clinical practice.
    DOI:  https://doi.org/10.1038/s41420-023-01472-4
  11. Front Oncol. 2023 ;13 1131259
    Multiomics technologies for comprehensive tumor microenvironment analysis in triple-negative breast cancer under neoadjuvant chemotherapy.
    Gang Wang, Yao Yao, Huanhuan Huang, Jun Zhou, Chao Ni.
      Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes and is characterized by abundant infiltrating immune cells within the microenvironment. As standard care, chemotherapy remains the fundamental neoadjuvant treatment in TNBC, and there is increasing evidence that supplementation with immune checkpoint inhibitors may potentiate the therapeutic efficiency of neoadjuvant chemotherapy (NAC). However, 20-60% of TNBC patients still have residual tumor burden after NAC and require additional chemotherapy; therefore, it is critical to understand the dynamic change in the tumor microenvironment (TME) during treatment to help improve the rate of complete pathological response and long-term prognosis. Traditional methods, including immunohistochemistry, bulk tumor sequencing, and flow cytometry, have been applied to elucidate the TME of breast cancer, but the low resolution and throughput may overlook key information. With the development of diverse high-throughput technologies, recent reports have provided new insights into TME alterations during NAC in four fields, including tissue imaging, cytometry, next-generation sequencing, and spatial omics. In this review, we discuss the traditional methods and the latest advances in high-throughput techniques to decipher the TME of TNBC and the prospect of translating these techniques to clinical practice.
    Keywords:  multi-omics; neoadjuvant chemotherapy; single-cell analysis; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1131259
  12. J Immunother Cancer. 2023 Jun;pii: e006611. [Epub ahead of print]11(6):
    Robust IL-2-dependent antitumor immunotherapy requires targeting the high-affinity IL-2R on tumor-specific CD8+ T cells.
    Kathryn M LaPorte, Rosmely Hernandez, Alicia Santos Savio, Thomas R Malek.
      BACKGROUND: Development of interleukin (IL)-2-dependent antitumor responses focus on targeting the intermediate affinity IL-2R to stimulate memory-phenotypic CD8+ T and natural killer (NK) cells while minimizing regulatory T cell (Treg) expansion. However, this approach may not effectively engage tumor-specific T effector cells. Since tumor-antigen specific T cells upregulate the high-affinity IL-2R, we tested an IL-2 biologic, mouse IL-2/CD25, with selectivity toward the high-affinity IL-2R to support antitumor responses to tumors that vary in their immunogenicity.METHODS: Mice were first implanted with either CT26, MC38, B16.F10, or 4T1 and after a tumor mass developed, they were treated with high-dose (HD) mouse (m)IL-2/CD25 alone or in combination with anti-programmed cell death protein-1 (PD-1) checkpoint blockade. Tumor growth was monitored and in parallel the immune signature in the tumor microenvironment (TME) was determined by a combination of multiparameter flow cytometry, functional assays, and enumeration of tumor-reactive T cells.
    RESULTS: We show that HD mIL-2/CD25, which preferentially stimulates the high-affinity IL-2R, but not IL-2/anti-IL-2 complexes with preferential activity toward the intermediate-affinity IL-2R, supports vigorous antitumor responses to immunogenic tumors as a monotherapy that were enhanced when combined with anti-PD-1. Treatment of CT26-bearing mice with HD mIL-2/CD25 led to a high CD8+:Treg ratio in the TME, increased frequency and function of tumor-specific CD8+ T effector cells with a less exhausted phenotype, and antitumor memory responses.
    CONCLUSIONS: Targeting the high-affinity IL-2R on tumor-specific T cells with HD mIL-2/CD25 alone or with PD-1 blockade supports antitumor responses, where the resulting memory response may afford long-term protection against tumor re-emergence.
    Keywords:  CD8-positive T-lymphocytes; cytokines; immune checkpoint inhibitors; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1136/jitc-2022-006611
  13. Biomark Res. 2023 Jun 07. 11(1): 63
    Review immune response of targeting CD39 in cancer.
    Yao Liu, Zhongliang Li, Xiaoguang Zhao, Jing Xiao, Jiacheng Bi, Xian-Yang Li, Guokai Chen, Ligong Lu.
      The ATP-adenosine pathway has emerged as a promising target for cancer therapy, but challenges remain in achieving effective tumor control. Early research focused on blocking the adenosine generating enzyme CD73 and the adenosine receptors A2AR or A2BR in cancer. However, recent studies have shown that targeting CD39, the rate-limiting ecto-enzyme of the ATP-adenosine pathway, can provide more profound anti-tumor efficacy by reducing immune-suppressive adenosine accumulation and increasing pro-inflammatory ATP levels. In addition, combining CD39 blocking antibody with PD-1 immune checkpoint therapy may have synergistic anti-tumor effects and improve patient survival. This review will discuss the immune components that respond to CD39 targeting in the tumor microenvironment. Targeting CD39 in cancer has been shown to not only decrease adenosine levels in the tumor microenvironment (TME), but also increase ATP levels. Additionally, targeting CD39 can limit the function of Treg cells, which are known to express high levels of CD39. With phase I clinical trials of CD39 targeting currently underway, further understanding and rational design of this approach for cancer therapy are expected.
    Keywords:  Adenosine pathway; CD39; Immune checkpoint blockade (ICB); PD-1
    DOI:  https://doi.org/10.1186/s40364-023-00500-w
  14. World J Gastrointest Oncol. 2023 May 15. 15(5): 757-775
    Immuno-oncology-microbiome axis of gastrointestinal malignancy.
    Quan Lin, Shi-Wei Guan, Hai-Bo Yu.
      Research on the relationship between the microbiome and cancer has been controversial for centuries. Recent works have discovered that the intratumor microbiome is an important component of the tumor microenvironment (TME). Intratumor bacteria, the most studied intratumor microbiome, are mainly localized in tumor cells and immune cells. As the largest bacterial reservoir in human body, the gut microbiome may be one of the sources of the intratumor microbiome in gastrointestinal malignancies. An increasing number of studies have shown that the gut and intratumor microbiome play an important role in regulating the immune tone of tumors. Moreover, it has been recently proposed that the gut and intratumor microbiome can influence tumor progression by modulating host metabolism and the immune and immune tone of the TME, which is defined as the immuno-oncology-microbiome (IOM) axis. The proposal of the IOM axis provides a new target for the tumor microbiome and tumor immunity. This review aims to reveal the mechanism and progress of the gut and intratumor microbiome in gastrointestinal malignancies such as esophageal cancer, gastric cancer, liver cancer, colorectal cancer and pancreatic cancer by exploring the IOM axis. Providing new insights into the research related to gastrointestinal malignancies.
    Keywords:  Gastrointestinal malignancy; Gut microbiome; Immunity; Intratumor microbiome; Therapy; Tumor microenvironment
    DOI:  https://doi.org/10.4251/wjgo.v15.i5.757
  15. Front Immunol. 2023 ;14 1194020
    The role of tumor-infiltrating lymphocytes in triple-negative breast cancer and the research progress of adoptive cell therapy.
    Ruonan Li, Lili Cao.
      The treatment outcome of breast cancer is closely related to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Triple-negative breast cancer (TNBC) lacking ER, PR, and HER2 expression has limited treatment options and a poor prognosis. Tumor-infiltrating lymphocytes (TILs) play a role in promoting or resisting tumors by affecting the tumor microenvironment and are known as key regulators in breast cancer progression. However, treatments for TNBC (e.g., surgery, chemotherapy and radiotherapy) have non-satisfaction's curative effect so far. This article reviews the role of different types of TILs in TNBC and the research progress of adoptive cell therapy, aiming to provide new therapeutic approaches for TNBC.
    Keywords:  adoptive cell therapy (ACT); breast cancer; solid tumor; triple-negative breast cancer (TNBC); tumor-infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.3389/fimmu.2023.1194020
  16. Oncol Lett. 2023 Jul;26(1): 281
    Combination of CAR‑T cell therapy and radiotherapy: Opportunities and challenges in solid tumors (Review).
    Liqiang Zhong, Yi Li, Tobias Achu Muluh, Yongsheng Wang.
      Chimeric antigen receptor (CAR) T cell therapy has emerged as a new and breakthrough cancer immunotherapy. Although CAR-T cell therapy has made significant progress clinically in patients with refractory or drug-resistant hematological malignancies, there are numerous challenges in its application to solid tumor therapy, including antigen escape, severe toxic reactions, abnormal vascularization, tumor hypoxia, insufficient infiltration of CAR-T cells and immunosuppression. As a conventional mode of anti-tumor therapy, radiotherapy has shown promising effects in combination with CAR-T cell therapy by enhancing the specific immunity of endogenous target antigens, which promoted the infiltration and expansion of CAR-T cells and improved the hypoxic tumor microenvironment. This review focuses on the obstacles to the application of CAR-T technology in solid tumor therapy, the potential opportunities and challenges of combined radiotherapy and CAR-T cell therapy, and the review of recent literature to evaluate the best combination for the treatment of solid tumors.
    Keywords:  CAR-T cell therapy; immunotherapy; radiotherapy; solid tumor clinical trials
    DOI:  https://doi.org/10.3892/ol.2023.13867
This page is being maintained by Thomas Krichel. It was last updated on 2023‒06‒11 at 17:02:32.