Novel Advances in Cancer Immunology: From Molecular Mechanisms to Therapeutic Applications

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cellular Immunology".

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Editors


E-Mail Website
Collection Editor
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, P.O. Box 39040, Tel Aviv 6997801, Israel
Interests: cancer immunology; tumor ablation and in situ immunostimulation; alpha-particle-based radiotherapy
Special Issues, Collections and Topics in MDPI journals

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Collection Editor
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00166 Rome, Italy
Interests: IL-33 pathway in cancer; eosinophils in tumor microenvironment; type I interferon pathways in cancer; tumor mouse models; organs-on-chip systems
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Collection Editor
1. The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA
2. The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA 90095, USA
Interests: NK cells; tumor immunology; cancer immunotherapy
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Collection Editor
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, The Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
Interests: nanocarrier

Topical Collection Information

Dear Colleagues,

Immune cells are important components of the tumor microenvironment, where they play a prominent role in favoring or contrasting cancer progression through direct and indirect activities. Cancer immunology is a growing field in charge of investigating the complex mechanisms and interactions between immune and cancer cells, with the aim of identifying therapeutic targets for immunotherapy-based approaches, as well as their possible combination with other anticancer treatment modalities. A previous Topical Collection, entitled “Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities”, was very successful, and comprises 29 papers and reviews concerning various aspects of cancer immunology. However, cancer immunology is a vast and dynamic field, making it difficult to cover in one Topical Collection. Therefore, we aim to work towards creating an additional Topical Collection on this topic.

This Topical Collection of Cells aims to present research articles and reviews expanding the scope of tumor immunology and its applications. Articles should focus on cellular and molecular mechanisms, whether immunological, tumor-cell-related or tumor-microenvironment-derived, involved in cancer elimination or progression. This Topical Collection also aims to provide data from clinical and translational research on how such mechanisms may be translated to immunotherapy and combined therapeutic approaches. All scientists working in these fields are cordially invited to submit their manuscripts.

All papers will be published on an ongoing basis with full open access. We look forward to receiving your interesting contributions.

Prof. Dr. Yona Keisari
Dr. Fabrizio Mattei
Dr. Anahid Jewett
Prof. Dr. Luyuan Li
Collection Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antitumor immunity
  • advanced in vitro cancer models
  • advanced in vivo models for translational research
  • cancer genomics
  • cancer metastasis
  • cancer stem cells and stemness in cancer
  • cell-based strategies: CART and CAR-NK
  • chemokines and chemokine receptors
  • chemotherapy
  • combination therapies
  • cytokines and cytokine receptors
  • drug repurposing
  • epigenetic modifications and immunotherapy
  • exosomes and cancer
  • molecular pathways in cancer
  • immunosuppression
  • immune cells in cancer
  • immune checkpoint inhibitors
  • immunotherapy
  • inflammation and cancer
  • immunodeficiencies and cancer
  • immunomodulation and targeted therapies
  • intratumor heterogeneity
  • mechanisms of carcinogenesis
  • novel biomarkers
  • microbiomes and immunotherapy
  • oncogenes
  • tumor suppressor genes
  • oncolytic viruses
  • radiotherapy
  • small-molecule immunomodulators
  • translational and clinical research
  • resistance to conventional therapies
  • therapeutic targets in cancer
  • tumor microenvironment
  • tumor animal models
  • tumor vaccines

Published Papers (8 papers)

2024

Jump to: 2023

17 pages, 2412 KiB  
Article
A Novel Protozoa Parasite-Derived Protein Adjuvant Is Effective in Immunization with Cancer Cells to Activate the Cancer-Specific Protective Immunity and Inhibit the Cancer Growth in a Murine Model of Colorectal Cancer
by Rajesh Mani, Chloe G. Martin, Kanal E. Balu, Qingding Wang, Piotr Rychahou, Tadahide Izumi, B. Mark Evers and Yasuhiro Suzuki
Cells 2024, 13(2), 111; https://doi.org/10.3390/cells13020111 - 6 Jan 2024
Viewed by 1313
Abstract
Cancer-specific CD8+ cytotoxic T cells play important roles in preventing cancer growth, and IFN-γ, in addition to IL-12 and type I interferon, is critical for activating CD8+ cytotoxic T cells. We recently identified the capability of the amino-terminus region of dense [...] Read more.
Cancer-specific CD8+ cytotoxic T cells play important roles in preventing cancer growth, and IFN-γ, in addition to IL-12 and type I interferon, is critical for activating CD8+ cytotoxic T cells. We recently identified the capability of the amino-terminus region of dense granule protein 6 (GRA6Nt) of Toxoplasma gondii, an intracellular protozoan parasite, to activate IFN-γ production of microglia, a tissue-resident macrophage population. Therefore, in the present study, we examined whether recombinant GRA6Nt protein (rGRA6Nt) functions as an effective adjuvant to potently activate cancer-specific protective immunity using a murine model of MC38 colorectal cancer (CRC). When mice were immunized with non-replicable (either treated with mitomycin C or irradiated by X-ray) MC38 CRC cells in combination with rGRA6Nt adjuvant and received a challenge implantation of replication-capable MC38 tumor cells, those mice markedly inhibited the growth of the implanted tumors in association with a two-fold increase in CD8+ T cell density within the tumors. In addition, CD8+ T cells of the immunized mice secreted significantly increased amounts of granzyme B, a key mediator of the cytotoxic activity of CD8+ T cells, and IFN-γ in response to MC38 CRC cells in vitro when compared to the T cells from unimmunized mice. Notably, the protective effects of the immunization were specific to MC38 CRC cells, as the immunized mice did not exhibit a significantly inhibited growth of EL4 lymphoma tumors. These results indicate that rGRA6Nt is a novel and effective protein adjuvant when used in immunizations with non-replicable cancer cells to potently activate the protective immunity specifically against the cancer cells employed in the immunization. Full article
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2023

Jump to: 2024

15 pages, 3985 KiB  
Article
Intratumoral Administration of High-Concentration Nitric Oxide and Anti-mPD-1 Treatment Improves Tumor Regression Rates and Survival in CT26 Tumor-Bearing Mice
by Hila Confino, Yogev Sela, Yana Epshtein, Lidor Malka, Matan Goldshtein, Selena Chaisson, Steve Lisi, Amir Avniel, Jedidiah Mercer Monson and Frederick M. Dirbas
Cells 2023, 12(20), 2439; https://doi.org/10.3390/cells12202439 - 11 Oct 2023
Viewed by 1408
Abstract
Background: Immune checkpoint inhibitors have transformed clinical oncology. However, their use is limited as response is observed in only ~20–50% of patients. Previously, we demonstrated that treating CT26 tumor-bearing mice with ultra-high-concentration gaseous nitric oxide (UNO) followed by tumor resection stimulated antitumor immune [...] Read more.
Background: Immune checkpoint inhibitors have transformed clinical oncology. However, their use is limited as response is observed in only ~20–50% of patients. Previously, we demonstrated that treating CT26 tumor-bearing mice with ultra-high-concentration gaseous nitric oxide (UNO) followed by tumor resection stimulated antitumor immune responses. Accordingly, UNO may improve tumor response to immune checkpoint inhibitors. Here, we investigated the ability of UNO to improve the efficacy of a programmed cell death protein-1 (PD-1) antibody in vitro and in treating CT26 tumor-bearing mice. Methods: CT26 cells were injected into the flank of Balb/c mice (n = 15–16 per group). On day 6, CT26 cells were injected into the contralateral flank, and anti-mPD-1 injections commenced. Primary tumors were treated with intratumoral UNO on day 8. Tumor volume, response rates, toxicity, and survival were monitored. Results: (1) Short exposure to 25,000–100,000 parts per million (ppm) UNO in vitro resulted in significant upregulation of PD-L1 expression on CT26 cells. (2) UNO treatment in vivo consistently reduced cell viability in CT26 tumors. (3) Treatment reduced regulatory T-cell (Treg) levels in the tumor and increased levels of systemic M1 macrophages. UNO responders had increased CD8+ T-cell tumor infiltration. (4) Nine days after treatment, primary tumor growth was significantly lower in the combination arm vs. anti-mPD-1 alone (p = 0.0005). (5) Complete tumor regression occurred in 8/15 (53%) of mice treated with a combination of 10 min UNO and anti-mPD-1, 100 days post-treatment, compared to 4/16 (25%) of controls treated with anti-mPD-1 alone (p = 0.1489). (6) There was no toxicity associated with UNO treatment. (7) Combination treatment showed a trend toward increased survival 100 days post-treatment compared to anti-mPD-1 alone (p = 0.0653). Conclusion: Combining high-concentration NO and immune checkpoint inhibitors warrants further assessment especially in tumors resistant to checkpoint inhibitor therapy. Full article
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23 pages, 9550 KiB  
Article
The Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Breast Cancer Are Regulated by N-Linked Glycosylation-Dependent Activation of STAT3 and STAT1
by Nofar Erlichman, Tsipi Meshel, Tamir Baram, Alaa Abu Raiya, Tamar Horvitz, Hagar Ben-Yaakov and Adit Ben-Baruch
Cells 2023, 12(19), 2338; https://doi.org/10.3390/cells12192338 - 23 Sep 2023
Cited by 2 | Viewed by 1379
Abstract
PD-L1 has been characterized as an inhibitory immune checkpoint, leading to the suppression of potential anti-tumor immune activities in many cancer types. In view of the relatively limited efficacy of immune checkpoint blockades against PD-L1 in breast cancer, our recent study addressed the [...] Read more.
PD-L1 has been characterized as an inhibitory immune checkpoint, leading to the suppression of potential anti-tumor immune activities in many cancer types. In view of the relatively limited efficacy of immune checkpoint blockades against PD-L1 in breast cancer, our recent study addressed the possibility that in addition to its immune-inhibitory functions, PD-L1 promotes the pro-metastatic potential of the cancer cells themselves. Indeed, our published findings demonstrated that PD-L1 promoted pro-metastatic functions of breast cancer cells in a cell-autonomous manner, both in vitro and in vivo. These functions fully depended on the integrity of the S283 intracellular residue of PD-L1. Here, using siRNAs and the S283A-PD-L1 variant, we demonstrate that the cell-autonomous pro-metastatic functions of PD-L1—tumor cell proliferation and invasion, and release of the pro-metastatic chemokine CXCL8—required the activation of STAT3 and STAT1 in luminal A and triple-negative breast cancer cells. The cell-autonomous pro-metastatic functions of PD-L1 were potently impaired upon inhibition of N-linked glycosylation (kifunensine). Site-specific mutants at each of the N-linked glycosylation sites of PD-L1 (N35, N192, N200, and N219) revealed that they were all required for PD-L1-induced pro-metastatic functions to occur; the N219 site was the main regulator of STAT3 and STAT1 activation, with accompanying roles for N192 and N200 (depending on the cell type). Using a T cell-independent mouse system, we found that cells expressing N35A-PD-L1 and N219A-PD-L1 had a significantly lower tumorigenic and metastatic potential than cells expressing WT-PD-L1. TCGA analyses revealed significant associations between reduced survival and high levels of α-mannosidase II (inferring on N-linked glycosylation) in breast cancer patients. These findings suggest that N-linked glycosylation of PD-L1 may be used to screen for patients who are at greater risk of disease progression, and that modalities targeting N-linked glycosylated PD-L1 may lead to the inhibition of its cell-autonomous pro-metastatic functions and to lower tumor progression in breast cancer. Full article
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16 pages, 976 KiB  
Article
Immunotherapy around the Clock: Impact of Infusion Timing on Stage IV Melanoma Outcomes
by Lisa Gonçalves, Duarte Gonçalves, Teresa Esteban-Casanelles, Tiago Barroso, Inês Soares de Pinho, Raquel Lopes-Brás, Miguel Esperança-Martins, Vanessa Patel, Sofia Torres, Rita Teixeira de Sousa, André Mansinho and Luís Costa
Cells 2023, 12(16), 2068; https://doi.org/10.3390/cells12162068 - 15 Aug 2023
Cited by 6 | Viewed by 1425
Abstract
Although the impact of circadian timing on immunotherapy has yet to be integrated into clinical practice, chronoimmunotherapy is an emerging and promising field as circadian oscillations are observed in immune cell numbers as well as the expression of immunotherapy targets, e.g., programmed cell [...] Read more.
Although the impact of circadian timing on immunotherapy has yet to be integrated into clinical practice, chronoimmunotherapy is an emerging and promising field as circadian oscillations are observed in immune cell numbers as well as the expression of immunotherapy targets, e.g., programmed cell death protein-1 and its ligand programmed death ligand 1. Concurrent retrospective studies suggest that morning infusions may lead to higher effectiveness of immune checkpoint inhibitors in melanoma, non-small cell lung cancer, and kidney cancer. This paper discusses the results of a retrospective study (2016–2022) exploring the impact of infusion timing on the outcomes of all 73 patients with stage IV melanoma receiving immunotherapy at a particular medical center. While the median overall survival (OS) was 24.2 months (95% confidence interval [CI] 9.04–39.8), for a median follow-up of 15.3 months, our results show that having more than 75% of infusions in the afternoon results in shorter median OS (14.9 vs. 38.1 months; hazard ratio 0.45 [CI 0.23–0.86]; p < 0.01) with more expressive impacts on particular subgroups: women, older patients, and patients with a lower tumor burden at the outset of immunotherapy. Our findings highlight the potential benefits of follow-up validation in prospective and translational randomized studies. Full article
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26 pages, 2639 KiB  
Review
Insight into Cancer Immunity: MHCs, Immune Cells and Commensal Microbiota
by Minting Wen, Yingjing Li, Xiaonan Qin, Bing Qin and Qiong Wang
Cells 2023, 12(14), 1882; https://doi.org/10.3390/cells12141882 - 18 Jul 2023
Cited by 2 | Viewed by 1674
Abstract
Cancer cells circumvent immune surveillance via diverse strategies. In accordance, a large number of complex studies of the immune system focusing on tumor cell recognition have revealed new insights and strategies developed, largely through major histocompatibility complexes (MHCs). As one of them, tumor-specific [...] Read more.
Cancer cells circumvent immune surveillance via diverse strategies. In accordance, a large number of complex studies of the immune system focusing on tumor cell recognition have revealed new insights and strategies developed, largely through major histocompatibility complexes (MHCs). As one of them, tumor-specific MHC-II expression (tsMHC-II) can facilitate immune surveillance to detect tumor antigens, and thereby has been used in immunotherapy, including superior cancer prognosis, clinical sensitivity to immune checkpoint inhibition (ICI) therapy and tumor-bearing rejection in mice. NK cells play a unique role in enhancing innate immune responses, accounting for part of the response including immunosurveillance and immunoregulation. NK cells are also capable of initiating the response of the adaptive immune system to cancer immunotherapy independent of cytotoxic T cells, clearly demonstrating a link between NK cell function and the efficacy of cancer immunotherapies. Eosinophils were shown to feature pleiotropic activities against a variety of solid tumor types, including direct interactions with tumor cells, and accessorily affect immunotherapeutic response through intricating cross-talk with lymphocytes. Additionally, microbial sequencing and reconstitution revealed that commensal microbiota might be involved in the modulation of cancer progression, including positive and negative regulatory bacteria. They may play functional roles in not only mucosal modulation, but also systemic immune responses. Here, we present a panorama of the cancer immune network mediated by MHCI/II molecules, immune cells and commensal microbiota and a discussion of prospective relevant intervening mechanisms involved in cancer immunotherapies. Full article
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20 pages, 2990 KiB  
Article
Fundamental Characterization of Antibody Fusion-Single-Chain TNF Recombinant Proteins Directed against Costimulatory TNF Receptors Expressed by T-Lymphocytes
by Hodaka Nagai, Mitsuki Azuma, Ayaka Sato, Nagito Shibui, Sayaka Ogawara, Yuta Tsutsui, Ayano Suzuki, Tomomi Wakaizumi, Aya Ito, Shimpei Matsuyama, Masashi Morita, Mari Hikosaka Kuniishi, Naoto Ishii and Takanori So
Cells 2023, 12(12), 1596; https://doi.org/10.3390/cells12121596 - 9 Jun 2023
Viewed by 1729
Abstract
The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference [...] Read more.
The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc−scOX40L, Fc−sc4-1BBL, Fc−scCD27L (CD70) and Fc−scGITRL. Without intentional cross-linking, these soluble Fc−scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4+ and CD8+ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc−scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc−scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins. Full article
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26 pages, 3983 KiB  
Article
The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway
by Sivan Izraely, Shlomit Ben-Menachem, Sapir Malka, Orit Sagi-Assif, Matias A. Bustos, Orit Adir, Tsipi Meshel, Maharrish Chelladurai, Suyeon Ryu, Romela I. Ramos, Metsada Pasmanik-Chor, Dave S. B. Hoon and Isaac P. Witz
Cells 2023, 12(11), 1513; https://doi.org/10.3390/cells12111513 - 30 May 2023
Cited by 4 | Viewed by 1803
Abstract
Previous studies from our lab demonstrated that the crosstalk between brain-metastasizing melanoma cells and microglia, the macrophage-like cells of the central nervous system, fuels progression to metastasis. In the present study, an in-depth investigation of melanoma-microglia interactions elucidated a pro-metastatic molecular mechanism that [...] Read more.
Previous studies from our lab demonstrated that the crosstalk between brain-metastasizing melanoma cells and microglia, the macrophage-like cells of the central nervous system, fuels progression to metastasis. In the present study, an in-depth investigation of melanoma-microglia interactions elucidated a pro-metastatic molecular mechanism that drives a vicious melanoma-brain-metastasis cycle. We employed RNA-Sequencing, HTG miRNA whole transcriptome assay, and reverse phase protein arrays (RPPA) to analyze the impact of melanoma-microglia interactions on sustainability and progression of four different human brain-metastasizing melanoma cell lines. Microglia cells exposed to melanoma-derived IL-6 exhibited upregulated levels of STAT3 phosphorylation and SOCS3 expression, which, in turn, promoted melanoma cell viability and metastatic potential. IL-6/STAT3 pathway inhibitors diminished the pro-metastatic functions of microglia and reduced melanoma progression. SOCS3 overexpression in microglia cells evoked microglial support in melanoma brain metastasis by increasing melanoma cell migration and proliferation. Different melanomas exhibited heterogeneity in their microglia-activating capacity as well as in their response to microglia-derived signals. In spite of this reality and based on the results of the present study, we concluded that the activation of the IL-6/STAT3/SOCS3 pathway in microglia is a major mechanism by which reciprocal melanoma-microglia signaling engineers the interacting microglia to reinforce the progression of melanoma brain metastasis. This mechanism may operate differently in different melanomas. Full article
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25 pages, 2487 KiB  
Review
Recent Emerging Immunological Treatments for Primary Brain Tumors: Focus on Chemokine-Targeting Immunotherapies
by Alessio Ardizzone, Rossella Basilotta, Alessia Filippone, Lelio Crupi, Marika Lanza, Sofia Paola Lombardo, Cristina Colarossi, Dorotea Sciacca, Salvatore Cuzzocrea, Emanuela Esposito and Michela Campolo
Cells 2023, 12(6), 841; https://doi.org/10.3390/cells12060841 - 8 Mar 2023
Cited by 4 | Viewed by 1972
Abstract
Primary brain tumors are a leading cause of death worldwide and are characterized by extraordinary heterogeneity and high invasiveness. Current drug and radiotherapy therapies combined with surgical approaches tend to increase the five-year survival of affected patients, however, the overall mortality rate remains [...] Read more.
Primary brain tumors are a leading cause of death worldwide and are characterized by extraordinary heterogeneity and high invasiveness. Current drug and radiotherapy therapies combined with surgical approaches tend to increase the five-year survival of affected patients, however, the overall mortality rate remains high, thus constituting a clinical challenge for which the discovery of new therapeutic strategies is needed. In this field, novel immunotherapy approaches, aimed at overcoming the complex immunosuppressive microenvironment, could represent a new method of treatment for central nervous system (CNS) tumors. Chemokines especially are a well-defined group of proteins that were so named due to their chemotactic properties of binding their receptors. Chemokines regulate the recruitment and/or tissue retention of immune cells as well as the mobilization of tumor cells that have undergone epithelial–mesenchymal transition, promoting tumor growth. On this basis, this review focuses on the function and involvement of chemokines and their receptors in primary brain tumors, specifically examining chemokine-targeting immunotherapies as one of the most promising strategies in neuro-oncology. Full article
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