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Liao S, Huang J, Lupala CS, Li X, Li X, Li N. Identification of the B7-H3 Interaction Partners Using a Proximity Labeling Strategy. Int J Mol Sci 2025; 26:1731. [PMID: 40004194 PMCID: PMC11855656 DOI: 10.3390/ijms26041731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/17/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
B7 homolog 3 (B7-H3) has emerged as a promising target for cancer therapy due to its high expression in various types of cancer cells. It not only regulates the activity of immune cells but also modulates the signal transduction and metabolism of cancer cells. However, the specific interaction partners of B7-H3 still remain unclear, limiting a comprehensive understanding of the precise role of B7-H3 in cancer progression. In this study, we report that B7-H3 can bind to resting Raji cells, stimulated THP-1 cells, and even PC3 prostate cancer cells through its IgV domain alone. Furthermore, to identify the potential interaction partners of B7-H3 on these cells, we adopted an ascorbate peroxidase 2 (APEX2)-based proximity labeling strategy, which revealed about 10 key potential interaction partners. Interestingly, our results suggest that CD45 could be a putative receptor for B7-H3 on Raji cells, while the epidermal growth factor receptor (EGFR) could closely interact with B7-H3 on PC3 cells. Based on further computational structure modeling studies, we show that B7-H3 can bind to the epidermal growth factor (EGF) binding pocket of EGFR-surprisingly, with a stronger affinity than EGF itself. Overall, our study provides an effective approach to identifying B7-H3 interaction partners in both immune and cancer cell lines.
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Affiliation(s)
- Shujie Liao
- State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (S.L.); (J.H.); (C.S.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jiamin Huang
- State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (S.L.); (J.H.); (C.S.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Cecylia S. Lupala
- State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (S.L.); (J.H.); (C.S.L.)
| | - Xiangcheng Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China;
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
| | - Xuefei Li
- State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (S.L.); (J.H.); (C.S.L.)
| | - Nan Li
- State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (S.L.); (J.H.); (C.S.L.)
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2
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Xia L, Wu Y, Ren Y, Wang Z, Zhou N, Zhou W, Zhou L, Jia L, He C, Meng X, Zhu H, Yang Z. A whole-body imaging technique for tumor-specific diagnostics and screening of B7H3-targeted therapies. J Clin Invest 2025; 135:e186388. [PMID: 39847434 PMCID: PMC11910224 DOI: 10.1172/jci186388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2025] Open
Abstract
BACKGROUNDB7H3, also known as CD276, is notably overexpressed in various malignant tumor cells in humans, with extremely high expression rates. The development of a radiotracer that targets B7H3 may provide a universal tumor-specific imaging agent and allow the noninvasive assessment of the whole-body distribution of B7H3-expressing lesions.METHODSWe enhanced and optimized the structure of an affibody (ABY) that targets B7H3 to create the radiolabeled radiotracer [68Ga]Ga-B7H3-BCH, and then, we conducted both foundational experiments and clinical translational studies.RESULTS[68Ga]Ga-B7H3-BCH exhibited high affinity (equilibrium dissociation constant [KD] = 4.5 nM), and it was taken up in large amounts by B7H3-transfected cells (A549CD276 and H1975CD276 cells); these phenomena were inhibited by unlabeled precursors. Moreover, PET imaging of multiple xenograft models revealed extensive [68Ga]Ga-B7H3-BCH uptake by tumors. In a clinical study including 20 patients with malignant tumors, the [68Ga]Ga-B7H3-BCH signal aggregated in both primary and metastatic lesions, surpassing fluorine-18 fluorodeoxyglucose (18F-FDG) in overall diagnostic efficacy for tumors (85.0% vs. 81.7%), including differentiated hepatocellular and metastatic gastric cancers. A strong correlation between B7H3 expression and [68Ga]Ga-B7H3-BCH uptake in tumors was observed, and B7H3 expression was detected with 84.38% sensitivity and 100% specificity when a maximum standardized uptake value (SUVmax) of 3.85 was set as the cutoff value. Additionally, B7H3-specific PET imaging is expected to predict B7H3 expression levels in tumor cells, intratumoral stroma, and peritumoral tissues.CONCLUSIONIn summary, [68Ga]Ga-B7H3-BCH has potential for the noninvasive identification of B7H3 expression in systemic lesions in patients with malignant tumors. This agent has prospects for improving pretreatment evaluation, predicting therapeutic responses, and monitoring resistance to therapy in patients with malignancies.TRIAL REGISTRATIONClinicalTrials.gov NCT06454955.FUNDINGThis research was financially supported by the Natural Science Foundation of Beijing Municipality (no. 7242266), the National Natural Science Foundation of China (no. 82202201), and the Young Elite Scientists Sponsorship Program by China Association for Science and Technology (CAST) (no. YESS20220230).
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Affiliation(s)
- Lei Xia
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Research, Investigation and Evaluation of Radiopharmaceuticals, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China and
| | - Yan Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Yanan Ren
- Department of Nuclear Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Zhen Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Hepato-Pancreato-Biliary Surgery, Sarcoma Center, Peking University Cancer Hospital and Institute, Beijing, China
| | - Nina Zhou
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Research, Investigation and Evaluation of Radiopharmaceuticals, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China and
| | - Wenyuan Zhou
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Research, Investigation and Evaluation of Radiopharmaceuticals, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China and
| | - Lixin Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Ling Jia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Chengxue He
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Research, Investigation and Evaluation of Radiopharmaceuticals, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China and
| | - Xiangxi Meng
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Research, Investigation and Evaluation of Radiopharmaceuticals, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China and
| | - Hua Zhu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Research, Investigation and Evaluation of Radiopharmaceuticals, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China and
| | - Zhi Yang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Research, Investigation and Evaluation of Radiopharmaceuticals, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China and
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Sutton MN, Glazer SE, Al Zaki A, Napoli A, Yang P, Bhosale P, Liu J, Gammon ST, Piwnica-Worms D. Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.18.628944. [PMID: 39763965 PMCID: PMC11702627 DOI: 10.1101/2024.12.18.628944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
B7-H3 (CD276), a member of the B7-family of immune checkpoint proteins, has been shown to have immunological and non-immunological effects promoting tumorigenesis [1, 2] and expression correlates with poor prognosis for many solid tumors, including cervical, ovarian and breast cancers [3-6]. We recently identified a tumor-cell autochthonous tumorigenic role for dimerization of the 4Ig isoform of B7-H3 (4Ig-B7-H3) [7], where 4Ig-B7-H3 dimerization in cis activated tumor-intrinsic cellular proliferation and tumorigenesis pathways, providing a novel opportunity for therapeutic intervention. Herein, a live cell split-luciferase complementation strategy was used to visualize 4Ig-B7-H3 homodimerization in a high-throughput small molecule screen (HTS) to identify modulators of this protein-protein interaction (PPI). Notably, the HTS identified several compounds that converged on lipid metabolism (including HMG-CoA reductase inhibitors, also known as statins) as significant inhibitors of 4Ig-B7-H3 dimerization (p < 0.01). In vitro and in vivo murine studies provided evidence that statin-mediated disruption of 4Ig-B7-H3 dimerization was associated with anti-tumor effects. Statin-mediated anti-cancer efficacy was selective for B7-H3-expressing tumors and retrospective analysis of clinical tumor specimens supported the hypothesis that concurrent statin use enhanced clinical outcomes for patients in a B7-H3 restricted manner. Thus, disruption of 4Ig-B7-H3 dimerization provides an unanticipated molecular mechanism linking statin use in cancer therapy and prevention with immune checkpoint.
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Affiliation(s)
- Margie N. Sutton
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Sarah E. Glazer
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ajlan Al Zaki
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Arianna Napoli
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ping Yang
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Priya Bhosale
- Department of Abdominal Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Jinsong Liu
- Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Seth T. Gammon
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - David Piwnica-Worms
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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Lake JA, Woods E, Hoffmeyer E, Schaller KL, Cruz-Cruz J, Fernandez J, Tufa D, Kooiman B, Hall SC, Jones D, Hayashi M, Verneris MR. Directing B7-H3 chimeric antigen receptor T cell homing through IL-8 induces potent antitumor activity against pediatric sarcoma. J Immunother Cancer 2024; 12:e009221. [PMID: 39043604 PMCID: PMC11268054 DOI: 10.1136/jitc-2024-009221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Advances in pediatric oncology have occurred for some cancers; however, new therapies for sarcoma have been inadequate. Cellular immunotherapy using chimeric antigen receptor (CAR) T cells has shown dramatic benefits in leukemia, lymphoma, and multiple myeloma but has been far less successful in pediatric solid tumors such as rhabdomyosarcoma (RMS) and osteosarcoma (OS). Balancing issues of "on-target, off-tumor toxicity", investigators have identified B7-H3 as a broadly expressed tumor antigen with otherwise restricted expression on normal tissues. We hypothesized that rapid homing via a chemokine receptor and CAR engagement through B7-H3 would enhance CAR T cell efficacy in solid tumors. METHODS We generated B7-H3 CAR T cells that also express the Interleukin-8 (IL-8) receptor, CXCR2. Cytokine production, flow cytometry, Seahorse assays and RNA sequencing were used to compare the B7-H3 CXCR2 (BC2) CAR T cells with B7-H3 CAR T cells. We developed an IL-8 overexpressing human RMS mouse model to test homing and cytotoxicity in vivo. RESULTS We demonstrate that IL-8 is expressed by RMS and OS and expression significantly increases after radiation. Overexpression of an IL-8 receptor, CXCR2, on B7-H3 CAR T cells enhances homing into IL-8 expressing tumors, augments T cell metabolism and leads to significant tumor regression. CONCLUSION These findings warrant further investigation into the use of BC2 CAR T cells as a treatment for patients with RMS, OS and other B7-H3-expressing, IL-8 producing solid tumors.
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Affiliation(s)
- Jessica A Lake
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Elena Woods
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Eric Hoffmeyer
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kristin L Schaller
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Joselyn Cruz-Cruz
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Joseph Fernandez
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Dejene Tufa
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Benjamin Kooiman
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Spencer C Hall
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Dallas Jones
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Masanori Hayashi
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Michael R Verneris
- Department of Pediatric Hematology, Oncology, BMT, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Rosenkrans ZT, Erbe AK, Clemons NB, Feils AS, Medina-Guevara Y, Jeffery JJ, Barnhart TE, Engle JW, Sondel PM, Hernandez R. Targeting both GD2 and B7-H3 using bispecific antibody improves tumor selectivity for GD2-positive tumors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.23.595624. [PMID: 38853889 PMCID: PMC11160562 DOI: 10.1101/2024.05.23.595624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Objectives Disialoganglioside 2 (GD2), overexpressed by cancers such as melanoma and neuroblastoma, is a tumor antigen for targeted therapy. The delivery of conventional IgG antibody technologies targeting GD2 is limited clinically by its co-expression on nerves that contributes to toxicity presenting as severe neuropathic pain. To improve the tumor selectivity of current GD2-targeting approaches, a next-generation bispecific antibody targeting GD2 and B7-H3 (CD276) was generated. Methods Differential expression of human B7-H3 (hB7-H3) was transduced into GD2+ B78 murine melanoma cells and confirmed by flow cytometry. We assessed the avidity and selectivity of our GD2-B7-H3 targeting bispecific antibodies (INV34-6, INV33-2, and INV36-6) towards GD2+/hB7-H3- B78 cells relative to GD2+/hB7-H3+ B78 cells using flow cytometry and competition binding assays, comparing results an anti-GD2 antibody (dinutuximab, DINU). The bispecific antibodies, DINU, and a non-targeted bispecific control (bsAb CTRL) were conjugated with deferoxamine for radiolabeling with Zr-89 (t1/2 = 78.4 h). Using positron emission tomography (PET) studies, we evaluated the in vivo avidity and selectivity of the GD2-B7-H3 targeting bispecific compared to bsAb CTRL and DINU using GD2+/hB7-H3+ and GD2+/hB7-H3- B78 tumor models. Results Flow cytometry and competition binding assays showed that INV34-6 bound with high avidity to GD2+/hB7-H3+ B78 cells with high avidity but not GD2+/hB7-H3+ B78 cells. In comparison, no selectivity between cell types was observed for DINU. PET in mice bearing the GD2+/hB7-H3- and GD2+/hB7-H3+ B78 murine tumor showed similar biodistribution in normal tissues for [89Zr]Zr-Df-INV34-6, [89Zr]Zr-Df-bsAb CTRL, and [89Zr]Zr-Df-DINU. Importantly, [89Zr]Zr-Df-INV34-6 tumor uptake was selective to GD2+/hB7-H3+ B78 over GD2+/hB7-H3- B78 tumors, and substantially higher to GD2+/hB7-H3+ B78 than the non-targeted [89Zr]Zr-Df-bsAb CTRL control. [89Zr]Zr-Df-DINU displayed similar uptake in both GD2+ tumor models, with uptake comparable to [89Zr]Zr-Df-INV34-6 in the GD2+/hB7-H3+ B78 model. Conclusion The GD2-B7-H3 targeting bispecific antibodies successfully improved selectivity to cells expressing both antigens. This approach should address the severe toxicities associated with GD2-targeting therapies by reducing off-tumor GD2 binding in nerves. Continued improvements in bispecific antibody technologies will continue to transform the therapeutic biologics landscape.
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Affiliation(s)
- Zachary T. Rosenkrans
- Departments of Medical Physics and Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
| | - Amy K. Erbe
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Nathan B. Clemons
- Departments of Medical Physics and Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | | | - Yadira Medina-Guevara
- Departments of Medical Physics and Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Justin J. Jeffery
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
| | - Todd E. Barnhart
- Departments of Medical Physics and Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Jonathan W. Engle
- Departments of Medical Physics and Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
| | - Paul M. Sondel
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Reinier Hernandez
- Departments of Medical Physics and Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
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Gao C, Li X, Xu Y, Zhang T, Zhu H, Yao D. Recent advances in CAR-T cell therapy for acute myeloid leukaemia. J Cell Mol Med 2024; 28:e18369. [PMID: 38712978 PMCID: PMC11075639 DOI: 10.1111/jcmm.18369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 02/18/2024] [Accepted: 04/17/2024] [Indexed: 05/08/2024] Open
Abstract
Acute myeloid leukaemia (AML) is a fatal and refractory haematologic cancer that primarily affects adults. It interferes with bone marrow cell proliferation. Patients have a 5 years survival rate of less than 30% despite the availability of several treatments, including chemotherapy, allogeneic haematopoietic stem cell transplantation (Allo-HSCT), and receptor antagonist drugs. Allo-HSCT is the mainstay of acute myeloid leukaemia treatment. Although it does work, there are severe side effects, such as graft-versus-host disease (GVHD). In recent years, chimeric antigen receptor (CAR)-T cell therapies have made significant progress in the treatment of cancer. These engineered T cells can locate and recognize tumour cells in vivo and release a large number of effectors through immune action to effectively kill tumour cells. CAR-T cells are among the most effective cancer treatments because of this property. CAR-T cells have demonstrated positive therapeutic results in the treatment of acute myeloid leukaemia, according to numerous clinical investigations. This review highlights recent progress in new targets for AML immunotherapy, and the limitations, and difficulties of CAR-T therapy for AML.
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Affiliation(s)
- Chi Gao
- College of Life Science and HealthWuhan University of Science and TechnologyWuhanChina
| | - Xin Li
- College of BiotechnologyTianjin University of Science and TechnologyTianjinChina
| | - Yao Xu
- College of Life Science and HealthWuhan University of Science and TechnologyWuhanChina
| | - Tongcun Zhang
- College of Life Science and HealthWuhan University of Science and TechnologyWuhanChina
- Institute of Biology and MedicineWuhan University of Science and TechnologyWuhanChina
| | - Haichuan Zhu
- College of Life Science and HealthWuhan University of Science and TechnologyWuhanChina
| | - Di Yao
- College of Life Science and HealthWuhan University of Science and TechnologyWuhanChina
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Haugh A, Daud AI. Therapeutic Strategies in BRAF V600 Wild-Type Cutaneous Melanoma. Am J Clin Dermatol 2024; 25:407-419. [PMID: 38329690 DOI: 10.1007/s40257-023-00841-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2023] [Indexed: 02/09/2024]
Abstract
There have been many recent advances in melanoma therapy. While 50% of melanomas have a BRAF mutation and are a target for BRAF inhibitors, the remaining 50% are BRAF wild-type. Immune checkpoint inhibitors targeting PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and lymphocyte activated gene-3 (Lag-3) are all approved for the treatment of patients with advanced BRAF wild-type melanoma; however, treatment of this patient population following initial immune checkpoint blockade is a current therapeutic challenge given the lack of other efficacious options. Here, we briefly review available US FDA-approved therapies for BRAF wild-type melanoma and focus on developing treatment avenues for this heterogeneous group of patients. We review the basics of genomic features of both BRAF mutant and BRAF wild-type melanoma as well as efforts underway to develop new targeted therapies involving the mitogen-activated protein kinase (MAPK) pathway for patients with BRAF wild-type tumors. We then focus on novel immunotherapies, including developing checkpoint inhibitors and agonists, cytokine therapies, oncolytic viruses and tumor-infiltrating lymphocytes, all of which represent potential therapeutic avenues for patients with BRAF wild-type melanoma who progress on currently approved immune checkpoint inhibitors.
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Affiliation(s)
- Alexandra Haugh
- Department of Medicine, University of California San Francisco, 550 16th Street, 6809, San Francisco, CA, 94158, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Adil I Daud
- Department of Medicine, University of California San Francisco, 550 16th Street, 6809, San Francisco, CA, 94158, USA.
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
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8
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Ulitzka M, Harwardt J, Lipinski B, Tran H, Hock B, Kolmar H. Potent Apoptosis Induction by a Novel Trispecific B7-H3xCD16xTIGIT 2+1 Common Light Chain Natural Killer Cell Engager. Molecules 2024; 29:1140. [PMID: 38474651 DOI: 10.3390/molecules29051140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Valued for their ability to rapidly kill multiple tumor cells in succession as well as their favorable safety profile, NK cells are of increasing interest in the field of immunotherapy. As their cytotoxic activity is controlled by a complex network of activating and inhibiting receptors, they offer a wide range of possible antigens to modulate their function by antibodies. In this work, we utilized our established common light chain (cLC)-based yeast surface display (YSD) screening procedure to isolate novel B7-H3 and TIGIT binding monoclonal antibodies. The chicken-derived antibodies showed single- to low-double-digit nanomolar affinities and were combined with a previously published CD16-binding Fab in a 2+1 format to generate a potent NK engaging molecule. In a straightforward, easily adjustable apoptosis assay, the construct B7-H3xCD16xTIGIT showed potent apoptosis induction in cancer cells. These results showcase the potential of the TIGIT NK checkpoint in combination with activating receptors to achieve increased cytotoxic activity.
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Affiliation(s)
- Michael Ulitzka
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287 Darmstadt, Germany
| | - Julia Harwardt
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287 Darmstadt, Germany
| | - Britta Lipinski
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287 Darmstadt, Germany
| | - Hue Tran
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287 Darmstadt, Germany
| | - Björn Hock
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287 Darmstadt, Germany
| | - Harald Kolmar
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Str. 4, 64287 Darmstadt, Germany
- Centre of Synthetic Biology, Technical University of Darmstadt, 64283 Darmstadt, Germany
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Jiang Y, Liu J, Chen L, Qian Z, Zhang Y. A promising target for breast cancer: B7-H3. BMC Cancer 2024; 24:182. [PMID: 38326735 PMCID: PMC10848367 DOI: 10.1186/s12885-024-11933-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/29/2024] [Indexed: 02/09/2024] Open
Abstract
Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint.In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.
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Affiliation(s)
- Ying Jiang
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Jiayu Liu
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Lingyan Chen
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, 214000, China
| | - Zhiwen Qian
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, 214000, China
| | - Yan Zhang
- Department of Oncology, Wuxi Maternal and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China.
- Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, 214000, China.
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10
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Chen LC, Yang PC, Chen CY, Chiang SF, Chen TW, Chen WTL, Ke TW, Liang JA, Shiau A, Chao KSC, Huang KCY. Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma. J Cancer 2024; 15:1750-1761. [PMID: 38370387 PMCID: PMC10869969 DOI: 10.7150/jca.91089] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/18/2024] [Indexed: 02/20/2024] Open
Abstract
Despite advances in therapeutic strategies for colorectal cancer (CRC), CRC has a high disease incidence with significant morbidity and mortality worldwide. Notably, immunotherapy has shown limited efficacy in treating metastatic CRC, underscoring the need for alternative immunotherapeutic targets for the management of metastatic colorectal cancer (mCRC). In the present study, we evaluated the levels of the immune checkpoint proteins PD-L1, PD-L2 and B7-H3 in a large cohort retrospective study. We found that tumor B7-H3 (52.7%) was highly expressed in primary tumors compared to that in PD-L1 (33.6%) or PD-L2 (34.0%). Elevated B7-H3 expression was associated with advanced stage and the risk of distant metastasis and correlated with poor disease-free survival (DFS), suggesting that tumor B7-H3 was an independent prognostic factor associated with worse DFS in colon adenocarcinoma patients (COAD), especially high-risk COAD patients who received adjuvant chemotherapy. Furthermore, we found that B7-H3 significantly promoted cell proliferation and tumor growth in CRC. B7-H3 may stabilize EGFR to activate its downstream pathway for cancer cell proliferation and resistance to oxaliplatin (OXP). Dual targeting of B7-H3 and EGFR markedly rescued the susceptibility to chemotherapy in colorectal cancer cells in vitro and in vivo. Overall, these results showed that B7-H3 exhibited a high prevalence in COAD patients and was significantly associated with worse prognosis in COAD patients. Dual targeting of B7-H3 and EGFR signaling might be a potential therapeutic strategy for high-risk COAD patients.
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Affiliation(s)
- Liang-Chi Chen
- Department of Pathology, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Pei-Chen Yang
- Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Chia-Yi Chen
- Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Shu-Fen Chiang
- Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung 42055, Taiwan
| | - Tsung-Wei Chen
- Department of Pathology, Asia University Hospital, Asia University, Taichung 41354, Taiwan
| | - William Tzu-Liang Chen
- Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu 302, Taiwan
- Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Department of Surgery, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Tao-Wei Ke
- Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
| | - Ji-An Liang
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Radiotherapy, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - An‑Cheng Shiau
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 40402, Taiwan
| | - K. S. Clifford Chao
- Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Radiotherapy, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Kevin Chih-Yang Huang
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 40402, Taiwan
- Translation Research Core, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 40402, Taiwan
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11
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Sutton MN, Glazer SE, Muzzioli R, Yang P, Gammon ST, Piwnica-Worms D. Dimerization of the 4Ig isoform of B7-H3 in tumor cells mediates enhanced proliferation and tumorigenic signaling. Commun Biol 2024; 7:21. [PMID: 38182652 PMCID: PMC10770396 DOI: 10.1038/s42003-023-05736-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 12/20/2023] [Indexed: 01/07/2024] Open
Abstract
B7-H3 (CD276) has two isoforms (2Ig and 4Ig), no confirmed cognate receptor, and physiological functions that remain elusive. While differentially expressed on many solid tumors correlating with poor survival, mechanisms of how B7-H3 signals in cis (tumor cell) versus in trans (immune cell co-regulator) to elicit pro-tumorigenic phenotypes remain poorly defined. Herein, we characterized a tumorigenic and signaling role for tumor cell-expressed 4Ig-B7-H3, the dominant human isoform, in gynecological cancers that could be abrogated upon CRISPR/Cas9 knockout of B7-H3; tumorigenesis was rescued upon re-expression of 4Ig-B7-H3. Size exclusion chromatography revealed dimerization states for the extracellular domains of both human 4Ig- and murine 2Ig-B7-H3. mEGFP lifetimes of expressed 4Ig-B7-H3-mEGFP fusions determined by FRET-FLIM assays confirmed close-proximity interactions of 4Ig-B7-H3 and identified two distinct homo-FRET lifetime populations, consistent with monomeric and homo-dimer interactions. In live cells, bioluminescence imaging of 4Ig-B7-H3-mediated split luciferase complementation showed dimerization of 4Ig-B7-H3. To separate basal from dimer state activities in the absence of a known receptor, C-terminus (cytosolic) chemically-induced dimerization of 4Ig-B7-H3 increased tumor cell proliferation and cell activation signaling pathways (AKT, Jak/STAT, HIF1α, NF-κβ) significantly above basal expression of 4Ig-B7-H3 alone. These results revealed a new, dimerization-dependent intrinsic tumorigenic signaling role for 4Ig-B7-H3, likely acting in cis, and provide a therapeutically-actionable target for intervention of B7-H3-dependent tumorigenesis.
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Affiliation(s)
- Margie N Sutton
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sarah E Glazer
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - Riccardo Muzzioli
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - Ping Yang
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - Seth T Gammon
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA
| | - David Piwnica-Worms
- Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA.
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12
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Wu H, Liu C, Yuan Q, Qiao Y, Ding Y, Duan L, Li W, Zhang M, Zhang X, Jiang Y, Lu J, Dong Z, Wang T, Liu K, Zhao J. A novel Fc-enhanced humanized monoclonal antibody targeting B7-H3 suppresses the growth of ESCC. Oncoimmunology 2023; 12:2282250. [PMID: 38126034 PMCID: PMC10732625 DOI: 10.1080/2162402x.2023.2282250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 11/07/2023] [Indexed: 12/23/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor of the digestive tract with a low 5-year survival rate due to the lack of effective treatment methods. Although therapeutic monoclonal antibodies (mAbs) now play an important role in cancer therapy, effective targeted mAbs are still lacking for ESCC. B7-H3 is highly expressed in a variety of tumors and has emerged as a promising therapeutic target. Several mAbs against B7-H3 have advanced to clinical trials, but their development has not yet been pursued for ESCC. Here, we developed a humanized and Fc-engineered anti-B7H3 mAb 24F-Hu-mut2 and systematically evaluated its anti-tumor activity in vitro and in vivo. The 24F-Hu-mut2 was humanized and modified in Fc fragment to obtain stronger antibody-dependent cell-mediated cytotoxicity(ADCC) activity and nanomolar affinity. Furthermore, both of ESCC cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mice models indicated that 24F-Hu-mut2 displayed potent in vivo anti-tumor activity. In addition, a computational docking model showed that the mAb bound to IgC1 and IgC2 domain of B7-H3, which is closer to the cell membrane. Consistently, our ELISA results verified the binding of 24F-Hu-WT and IgC1 and IgC2. Our results indicate that 24F-Hu-mut2 has significant anti-ESCC activity both in vitro and in vivo, and this monoclonal antibody may be a promising antibody against ESCC and other B7-H3 overexpressing tumors.
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Affiliation(s)
- Huiting Wu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Chang Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Qiang Yuan
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Yan Qiao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Yongwei Ding
- Department of Pathophysiology, Shaoxing People Hospital, Shaoxing, China
| | - Lina Duan
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Wenjing Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Mengjia Zhang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Xuhua Zhang
- The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, China
| | - Yanan Jiang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Jing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Ziming Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
| | - Tao Wang
- Telethon Kids Institute, University of Western Australia, Perth, Australia
- The College of Nursing and Health, Zhengzhou University, Zhengzhou, China
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
| | - Jimin Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemo- prevention, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
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13
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Seo YR, Lee J, Ryu HS, Kim EG, Kim SH, Jeong J, Jung H, Jung Y, Kim HB, Jo YH, Kim YD, Jin MS, Lee YY, Kim KM, Yi EC. Lateral interactions between CD276 and CD147 are essential for stemness in breast cancer: a novel insight from proximal proteome analysis. Sci Rep 2023; 13:14242. [PMID: 37648771 PMCID: PMC10469185 DOI: 10.1038/s41598-023-41416-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 08/25/2023] [Indexed: 09/01/2023] Open
Abstract
Oncogenic cell-surface membrane proteins contribute to the phenotypic and functional characteristics of cancer stem cells (CSCs). We employed a proximity-labeling proteomic approach to quantitatively analyze the cell-surface membrane proteins in close proximity to CD147 in CSCs. Furthermore, we compared CSCs to non-CSCs to identify CSC-specific cell-surface membrane proteins that are closely interact with CD147 and revealed that lateral interaction between CD147 and CD276 concealed within the lipid raft microdomain in CSCs, confers resistance to docetaxel, a commonly used chemotherapy agent for various cancer types, including metastatic breast cancer. Moreover, we investigated the clinical relevance of CD147 and CD276 co-expression in HER2+ breast cancer (BC) and triple-negative breast cancer patients who underwent chemotherapy. We observed poor disease-free survival and Overall survival rates in patients of CD147 and CD276 (p = 0.04 and 0.08, respectively). Subsequent immunohistochemical analysis in independent cohorts of HER2+ BC support for the association between co-expression of CD147 and CD276 and a poor response to chemotherapy. Collectively, our study suggests that the lateral interaction between CD147 and its proximal partners, such as CD276, may serve as a poor prognostic factor in BC and a predictive marker for the critical phenotypic determinant of BC stemness.
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Affiliation(s)
- Yu Ri Seo
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Junghyeon Lee
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, Republic of Korea
- Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - EunHee G Kim
- Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - So Hyun Kim
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Jieun Jeong
- Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Hyeryeon Jung
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - YeoJin Jung
- Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Han Byeol Kim
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Yeon Hui Jo
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, Republic of Korea
| | - Yeong Dong Kim
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, Republic of Korea
| | - Min-Sun Jin
- Department of Pathology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Yong Yook Lee
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Kristine M Kim
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, Republic of Korea.
- Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.
| | - Eugene C Yi
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
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14
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Rasic P, Jeremic M, Jeremic R, Dusanovic Pjevic M, Rasic M, Djuricic SM, Milickovic M, Vukadin M, Mijovic T, Savic D. Targeting B7-H3-A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment. Molecules 2023; 28:molecules28083356. [PMID: 37110590 PMCID: PMC10145344 DOI: 10.3390/molecules28083356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood.
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Affiliation(s)
- Petar Rasic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
| | - Marija Jeremic
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Rada Jeremic
- Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Marija Dusanovic Pjevic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Milica Rasic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Slavisa M Djuricic
- Department of Clinical Pathology, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
- Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina
| | - Maja Milickovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Miroslav Vukadin
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
| | - Tanja Mijovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
| | - Djordje Savic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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15
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Fan S, Wang T, You F, Zhang T, Li Y, Ji C, Han Z, Sheng B, Zhai X, An G, Meng H, Yang L. B7-H3 chimeric antigen receptor-modified T cell shows potential for targeted treatment of acute myeloid leukaemia. Eur J Med Res 2023; 28:129. [PMID: 36941687 PMCID: PMC10026503 DOI: 10.1186/s40001-023-01049-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 02/07/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND AND AIMS Chimeric antigen receptor (CAR)-T cell therapy is a novel type of immunotherapy. However, the use of CAR-T cells to treat acute myeloid leukaemia (AML) has limitations. B7-H3 is expressed in several malignancies, including some types of AML cells. However, its expression in normal tissues is low. Therefore, B7-H3 is ideal for targeted AML therapy. MATERIALS AND METHODS First, we constructed B7-H3 CAR that can target B7-H3, and then constructed B7-H3-CAR-T cells in vitro, which were co-incubated with six AML cell lines expressing different levels of B7-H3, respectively. The toxicity and cytokines were detected by flow cytometry. In vivo, AML model was established in B-NSG mice to study the toxicity of B7-H3-CAR T on AML cells. RESULTS In vitro functional tests showed that B7-H3-CAR-T cells were cytotoxic to B7-H3-positive AML tumor cells and had good scavenging effect on B7-H3-expressing AML cell lines, and the cytokine results were consistent. In vivo, B7-H3-CAR-T cells significantly inhibited tumor cell growth in a mouse model of AML, prolonging mouse survival compared with controls. CONCLUSION B7-H3-CAR-T cells may serve as a novel therapeutic method for the targeted treatment of AML.
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Affiliation(s)
- Shuangshuang Fan
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Tian Wang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu, China
| | - Fengtao You
- PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, Jiangsu, China
| | - Tingting Zhang
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Yafen Li
- PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, Jiangsu, China
| | - Cheng Ji
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Zhichao Han
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Binjie Sheng
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Xiaochen Zhai
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Gangli An
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, China
| | - Huimin Meng
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China.
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, China.
| | - Lin Yang
- The Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu, China.
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, China.
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, Jiangsu, China.
- PersonGen BioTherapeutics (Suzhou) Co., Ltd., Suzhou, Jiangsu, China.
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16
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Guo C, Figueiredo I, Gurel B, Neeb A, Seed G, Crespo M, Carreira S, Rekowski J, Buroni L, Welti J, Bogdan D, Gallagher L, Sharp A, Fenor de la Maza MD, Rescigno P, Westaby D, Chandran K, Riisnaes R, Ferreira A, Miranda S, Calì B, Alimonti A, Bressan S, Nguyen AHT, Shen MM, Hawley JE, Obradovic A, Drake CG, Bertan C, Baker C, Tunariu N, Yuan W, de Bono JS. B7-H3 as a Therapeutic Target in Advanced Prostate Cancer. Eur Urol 2023; 83:224-238. [PMID: 36114082 DOI: 10.1016/j.eururo.2022.09.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/05/2022] [Accepted: 09/02/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND B7-H3 is a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers (PCs). Understanding its longitudinal expression at emergence of castration resistance and association with tumour genomics are critical to the development of and patient selection for B7-H3 targeted therapies. OBJECTIVE To characterise B7-H3 expression in same-patient hormone-sensitive (HSPC) and castration-resistant (CRPC) PC biopsies, associating this with PC genomics, and to evaluate the antitumour activity of an anti-B7-H3 antibody-drug conjugate (ADC) in human CRPC in vitro and in vivo. DESIGN, SETTING, AND PARTICIPANTS We performed immunohistochemistry and next-generation sequencing on a cohort of 98 clinically annotated CRPC biopsies, including 72 patients who also had HSPC biopsies for analyses. We analysed two CRPC transcriptome and exome datasets, and PC scRNASeq datasets. PC organoids (patient-derived xenograft [PDX]-derived organoids [PDX-Os]) were derived from PDXs generated from human CRPC biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We evaluated B7-H3 mRNA expression in relation to a panel of 770 immune-related genes, compared B7-H3 protein expression between same-patient HSPC and CRPC biopsies, determined associations with PC genomic alterations, and evaluated the antitumour activity of DS-7300a, a topoisomerase-1 inhibitor payload anti-B7-H3 ADC, in human PC cell lines, organoids (PDX-Os), and xenografts (PDXs) of different histologies, B7-H3 expressions, and genomics. RESULTS AND LIMITATIONS B7-H3 was among the most highly expressed immunomodulatory genes in CRPCs. Most CRPCs (93%) expressed B7-H3, and in patients who developed CRPC, B7-H3 expression was frequently expressed at the time of HSPC diagnosis (97%). Conversion from B7-H3 positive to negative, or vice versa, during progression from HSPC to CRPC was uncommon. CRPC with neuroendocrine features were more likely to be B7-H3 negative (28%) than adenocarcinomas. B7-H3 is overexpressed in tumours with defective DNA repair gene (ATM and BRCA2) alterations and is associated with ERG expression, androgen receptor (AR) expression, and AR activity signature. DS7300a had antitumour activity against B7-H3 expressing human PC models including cell lines, PDX-Os, and PDXs of adenocarcinoma and neuroendocrine histology. CONCLUSIONS The frequent overexpression of B7-H3 in CRPC compared with normal tissue and other B7 family members implicates it as a highly relevant therapeutic target in these diseases. Mechanisms driving differences in B7-H3 expression across genomic subsets warrant investigation for understanding the role of B7-H3 in cancer growth and for the clinical development of B7-H3 targeted therapies. PATIENT SUMMARY B7-H3, a protein expressed on the surface of the most lethal prostate cancers, in particular those with specific mutations, can be targeted using drugs that bind B7-H3. These findings are relevant for the development of such drugs and for deciding which patients to treat with these new drugs.
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Affiliation(s)
- Christina Guo
- The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK
| | | | - Bora Gurel
- The Institute of Cancer Research, London, UK
| | - Antje Neeb
- The Institute of Cancer Research, London, UK
| | - George Seed
- The Institute of Cancer Research, London, UK
| | | | | | | | | | - Jon Welti
- The Institute of Cancer Research, London, UK
| | | | | | - Adam Sharp
- The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Maria D Fenor de la Maza
- The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK
| | | | - Daniel Westaby
- The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Khobe Chandran
- The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK
| | | | | | | | - Bianca Calì
- Institute of Oncology Research, Oncology Institute of Southern Switzerland, Università della Svizzera Italiana, Bellinzona, Switzerland
| | - Andrea Alimonti
- Institute of Oncology Research, Oncology Institute of Southern Switzerland, Università della Svizzera Italiana, Bellinzona, Switzerland; Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland; Veneto Institute of Molecular Medicine, Padova, Italy
| | - Silvia Bressan
- Institute of Oncology Research, Oncology Institute of Southern Switzerland, Università della Svizzera Italiana, Bellinzona, Switzerland; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | | | - Michael M Shen
- Columbia University Irving Medical Center, New York, NY, USA
| | - Jessica E Hawley
- Columbia University Irving Medical Center, New York, NY, USA; University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | | | - Charles G Drake
- Columbia University Irving Medical Center, New York, NY, USA; Janssen Research, Spring House, PA, USA
| | | | - Chloe Baker
- The Institute of Cancer Research, London, UK
| | - Nina Tunariu
- The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK
| | - Wei Yuan
- The Institute of Cancer Research, London, UK
| | - Johann S de Bono
- The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK.
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17
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Dai L, Guo X, Xing Z, Tao Y, Liang W, Shi Z, Hu W, Zhou S, Wang X. Multi-omics analyses of CD276 in pan-cancer reveals its clinical prognostic value in glioblastoma and other major cancer types. BMC Cancer 2023; 23:102. [PMID: 36717836 PMCID: PMC9885708 DOI: 10.1186/s12885-023-10575-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 01/23/2023] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND CD276 (also known as B7-H3) is one of the most important immune checkpoints of the CD28 and B7 superfamily, and its abnormal expression is closely associated with various types of cancer. It has been shown that CD276 is able to inhibit the function of T cells, and that this gene may potentially be a promising immunotherapy target for different types of cancer. METHODS Since few systematic studies have been published on the role of CD276 in cancer to date, the present study has employed single-cell sequencing and bioinformatics methods to analyze the expression patterns, clinical significance, prognostic value, epigenetic alterations, DNA methylation level, tumor immune cell infiltration and immune functions of CD276 in different types of cancer. In order to analyze the potential underlying mechanism of CD276 in glioblastoma (GBM) to assess its prognostic value, the LinkedOmics database was used to explore the biological function and co-expression pattern of CD276 in GBM, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. In addition, a simple validation of the above analyses was performed using reverse transcription-quantitative (RT-q)PCR assay. RESULTS The results revealed that CD276 was highly expressed, and was often associated with poorer survival and prognosis, in the majority of different types of cancer. In addition, CD276 expression was found to be closely associated with T cell infiltration, immune checkpoint genes and immunoregulatory interactions between lymphoid and a non-lymphoid cell. It was also shown that the CD276 expression network exerts a wide influence on the immune activation of GBM. The expression of CD276 was found to be positively correlated with neutrophil-mediated immunity, although it was negatively correlated with the level of neurotransmitters, neurotransmitter transport and the regulation of neuropeptide signaling pathways in GBM. It is noteworthy that CD276 expression was found to be significantly higher in GBM compared with normal controls according to the RT-qPCR analysis, and the co-expression network, biological function and chemotherapeutic drug sensitivity of CD276 in GBM were further explored. In conclusion, the findings of the present study have revealed that CD276 is strongly expressed and associated with poor prognosis in most types of cancer, including GBM, and its expression is strongly associated with T-cell infiltration, immune checkpoint genes, and immunomodulatory interactions between lymphocytes and non-lymphoid cells. CONCLUSIONS Taken together, based on our systematic analysis, our findings have revealed important roles for CD276 in different types of cancers, especially GBM, and CD276 may potentially serve as a biomarker for cancer.
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Affiliation(s)
- Lirui Dai
- grid.460069.dDepartment of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052 China ,grid.207374.50000 0001 2189 3846Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450052 China ,Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan China
| | - Xuyang Guo
- grid.460069.dDepartment of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052 China ,grid.207374.50000 0001 2189 3846Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450052 China ,Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan China
| | - Zhe Xing
- grid.460069.dDepartment of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052 China ,grid.207374.50000 0001 2189 3846Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450052 China ,Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan China
| | - Yiran Tao
- grid.460069.dDepartment of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052 China ,grid.207374.50000 0001 2189 3846Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450052 China ,Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan China
| | - Wulong Liang
- grid.460069.dDepartment of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052 China ,Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan China
| | - Zimin Shi
- grid.460069.dDepartment of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052 China ,grid.207374.50000 0001 2189 3846Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450052 China ,Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan China
| | - Weihua Hu
- grid.460069.dDepartment of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052 China ,Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan China
| | - Shaolong Zhou
- grid.460069.dDepartment of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052 China ,Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan China
| | - Xinjun Wang
- grid.460069.dDepartment of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052 China ,grid.207374.50000 0001 2189 3846Institute of Neuroscience, Zhengzhou University, Zhengzhou, 450052 China ,Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan China
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Stanford University from across the Atlantic Ocean: an Italian Medical Student research experience. Eur J Nucl Med Mol Imaging 2023; 50:251-252. [PMID: 36357593 DOI: 10.1007/s00259-022-06033-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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D’Angelo A, Kilili H, Chapman R, Generali D, Tinhofer I, Luminari S, Donati B, Ciarrocchi A, Giannini R, Moretto R, Cremolini C, Pietrantonio F, Sobhani N, Bonazza D, Prins R, Song SG, Jeon YK, Pisignano G, Cinelli M, Bagby S, Urrutia AO. Immune-related pan-cancer gene expression signatures of patient survival revealed by NanoString-based analyses. PLoS One 2023; 18:e0280364. [PMID: 36649303 PMCID: PMC9844904 DOI: 10.1371/journal.pone.0280364] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
The immune system plays a central role in the onset and progression of cancer. A better understanding of transcriptional changes in immune cell-related genes associated with cancer progression, and their significance in disease prognosis, is therefore needed. NanoString-based targeted gene expression profiling has advantages for deployment in a clinical setting over RNA-seq technologies. We analysed NanoString PanCancer Immune Profiling panel gene expression data encompassing 770 genes, and overall survival data, from multiple previous studies covering 10 different cancer types, including solid and blood malignancies, across 515 patients. This analysis revealed an immune gene signature comprising 39 genes that were upregulated in those patients with shorter overall survival; of these 39 genes, three (MAGEC2, SSX1 and ULBP2) were common to both solid and blood malignancies. Most of the genes identified have previously been reported as relevant in one or more cancer types. Using Cibersort, we investigated immune cell levels within individual cancer types and across groups of cancers, as well as in shorter and longer overall survival groups. Patients with shorter survival had a higher proportion of M2 macrophages and γδ T cells. Patients with longer overall survival had a higher proportion of CD8+ T cells, CD4+ T memory cells, NK cells and, unexpectedly, T regulatory cells. Using a transcriptomics platform with certain advantages for deployment in a clinical setting, our multi-cancer meta-analysis of immune gene expression and overall survival data has identified a specific transcriptional profile associated with poor overall survival.
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Affiliation(s)
- Alberto D’Angelo
- Department of Life Sciences, University of Bath, Bath, United Kingdom
- Oncology Department, Royal United Hospital, Bath, United Kingdom
- * E-mail:
| | - Huseyin Kilili
- Milner Centre, Department of Life Sciences, University of Bath, Bath, United Kingdom
| | - Robert Chapman
- Department of Medicine, The Princess Alexandra Hospital, Harlow, United Kingdom
| | - Daniele Generali
- Multidisciplinary Unit of Breast Pathology and Translational Research, Cremona Hospital, Cremona, Italy
| | - Ingeborg Tinhofer
- Department of Radiooncology and Radiotherapy, Charite´ University Hospital, Berlin, Germany
| | - Stefano Luminari
- Hematology Unit, Azienda USL-IRCCS, Reggio Emilia, Italy
- Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Reggio Emilia, Italy
| | - Benedetta Donati
- Translational Research Laboratory, Azienda USL-IRCCS, Reggio Emilia, Italy
| | - Alessia Ciarrocchi
- Translational Research Laboratory, Azienda USL-IRCCS, Reggio Emilia, Italy
| | - Riccardo Giannini
- Department of Surgery, Clinical, Molecular and Critical Care Pathology, University of Pisa, Pisa, Italy
| | - Roberto Moretto
- Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | | | - Navid Sobhani
- Section of Epidemiology and Population Science, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Debora Bonazza
- Department of Medical, Surgical and Health Sciences, Cattinara Hospital, University of Trieste, Trieste, Italy
| | - Robert Prins
- Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America
| | - Seung Geun Song
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoon Kyung Jeon
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
| | | | - Mattia Cinelli
- Department of Life Sciences, University of Bath, Bath, United Kingdom
| | - Stefan Bagby
- Department of Life Sciences, University of Bath, Bath, United Kingdom
| | - Araxi O. Urrutia
- Milner Centre, Department of Life Sciences, University of Bath, Bath, United Kingdom
- Instituto de Ecologia, UNAM, Ciudad de Mexico, Mexico
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20
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Li C, Sun Z, Song Y, Zhang Y. Suppressive function of bone marrow-derived mesenchymal stem cell-derived exosomal microRNA-187 in prostate cancer. Cancer Biol Ther 2022; 23:1-14. [PMID: 36245088 PMCID: PMC9578467 DOI: 10.1080/15384047.2022.2123675] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Application of bone marrow-derived mesenchymal stem cell-derived exosomes (BMSC-exos) in cancer treatment has been widely studied. Here, we elaborated the function of BMSC-exos containing microRNA-187 (miR-187) in prostate cancer. Differentially expressed miRs and genes were screened with microarray analysis. The relationship between CD276 and miR-187 in prostate cancer was evaluated. Following miR-187 mimic/inhibitor or CD276 overexpression transfection, their actions in prostate cancer cell biological processes were analyzed. Prostate cancer cells were then exposed to BMSC-exos that were treated with either miR-187 mimic/inhibitor or CD276 overexpression for pinpointing the in vitro and in vivo effects of exosomal miR-187. miR-187 was poorly expressed while CD276 was significantly upregulated in prostate cancer. Additionally, restoring miR-187 inhibited the prostate cancer cell malignant properties by targeting CD276. Upregulation of miR-187 led to declines in CD276 expression and the JAK3-STAT3-Slug signaling pathway. Next, BMSC-exos carrying miR-187 contributed to repressed cell malignant features as well as limited tumorigenicity and tumor metastasis. Collectively, this study demonstrated that BMSC-derived exosomal miR-187 restrained prostate cancer by reducing CD276/JAK3-STAT3-Slug axis.
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Affiliation(s)
- Chuangui Li
- Department of Urology, Hebei Medical University, Shijiazhuang, P. R. China
| | - Zhen Sun
- Department of Urology, Songshan General Hospital, Chongqing, P. R. China
| | - Yajun Song
- Department of Urology, the Second Affiliated Hospital, Army Medical University, Chongqing, P. R. China,CONTACT Yajun Song Department of Urology, the Second Affiliated Hospital, Army Medical University, Chongqing, P. R. China
| | - Yong Zhang
- Department of Urology, Hebei Medical University, Shijiazhuang, P. R. China,Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China,Yong Zhang Department of Urology, Ministry of Education of China, Hebei Medical University, No. 361, Zhongshan East Road, Shijiazhuang050000, Hebei Province, P. R. China
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Fontes MS, Vargas Pivato de Almeida D, Cavalin C, Tagawa ST. Targeted Therapy for Locally Advanced or Metastatic Urothelial Cancer (mUC): Therapeutic Potential of Sacituzumab Govitecan. Onco Targets Ther 2022; 15:1531-1542. [PMID: 36575731 PMCID: PMC9790156 DOI: 10.2147/ott.s339348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022] Open
Abstract
Urothelial carcinoma is the second most frequent genitourinary malignancy. Despite the poor prognosis, new treatment options have emerged and have expanded the therapeutic landscape for the disease. Although major improvements have been achieved, many patients experience rapid disease progression and low responses in subsequent lines of therapy. Sacituzumab govitecan is an ADC that targets Trop-2, which is highly expressed in urothelial cancers. Promising results in early clinical trials have led to further drug development which confirmed encouraging efficacy. Sacituzumab govitecan has been given accelerated approval in 2021 for patients with locally advanced and metastatic urothelial cancer who previously received a platinum containing chemotherapy and either a programmed death receptor-1 or programmed death ligand inhibitor. The results are promising, with encouraging efficacy and safety, however responses are not universal. There is a growing comprehension of mechanisms of resistance and predictive biomarkers that are crucial to improving outcomes. In this review, we summarize the current knowledge on antibody-drug conjugates and the clinical findings that led to the approval of Sacituzumab govitecan and discuss the therapeutic potential of new combinations, mechanisms of resistance and predictive biomarkers.
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Affiliation(s)
- Mariane S Fontes
- Oncology Department, Oncoclinicas Group, Rio de Janeiro, Brazil
- LACOG, Latin American Cooperative Oncology Group, Brazil
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22
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Schorr C, Perna F. Targets for chimeric antigen receptor T-cell therapy of acute myeloid leukemia. Front Immunol 2022; 13:1085978. [PMID: 36605213 PMCID: PMC9809466 DOI: 10.3389/fimmu.2022.1085978] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy associated with high mortality rates (less than 30% 5-year survival). Despite advances in our understanding of the molecular mechanisms underpinning leukemogenesis, standard-of-care therapeutic approaches have not changed over the last couple of decades. Chimeric Antigen Receptor (CAR) T-cell therapy targeting CD19 has shown remarkable clinical outcomes for patients with acute lymphoblastic leukemia (ALL) and is now an FDA-approved therapy. Targeting of myeloid malignancies that are CD19-negative with this promising technology remains challenging largely due to lack of alternate target antigens, complex clonal heterogeneity, and the increased recognition of an immunosuppressive bone marrow. We carefully reviewed a comprehensive list of AML targets currently being used in both proof-of-concept pre-clinical and experimental clinical settings. We analyzed the expression profile of these molecules in leukemic as well normal tissues using reliable protein databases and data reported in the literature and we provide an updated overview of the current clinical trials with CAR T-cells in AML. Our study represents a state-of-art review of the field and serves as a potential guide for selecting known AML-associated targets for adoptive cellular therapies.
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Affiliation(s)
- Christopher Schorr
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States,Department of Biomedical Engineering, Purdue University Weldon School of Biomedical Engineering, West Lafayette, IN, United States
| | - Fabiana Perna
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States,*Correspondence: Fabiana Perna,
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Catalano M, Shabani S, Venturini J, Ottanelli C, Voltolini L, Roviello G. Lung Cancer Immunotherapy: Beyond Common Immune Checkpoints Inhibitors. Cancers (Basel) 2022; 14:6145. [PMID: 36551630 PMCID: PMC9777293 DOI: 10.3390/cancers14246145] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/27/2022] [Accepted: 11/27/2022] [Indexed: 12/15/2022] Open
Abstract
Immunotherapy is an ever-expanding field in lung cancer treatment research. Over the past two decades, there has been significant progress in identifying immunotherapy targets and creating specific therapeutic agents, leading to a major paradigm shift in lung cancer treatment. However, despite the great success achieved with programmed death protein 1/ligand 1 (PD-1/PD-L1) monoclonal antibodies and with anti-PD-1/PD-L1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), only a minority of lung cancer patients respond to treatment, and of these many subsequently experience disease progression. In addition, immune-related adverse events sometimes can be life-threatening, especially when anti-CTLA-4 and anti-PD-1 are used in combination. All of this prompted researchers to identify novel immune checkpoints targets to overcome these limitations. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin (Ig) and Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (TIM-3) are promising molecules now under investigation. This review aims to outline the current role of immunotherapy in lung cancer and to examine efficacy and future applications of the new immune regulating molecules.
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Affiliation(s)
- Martina Catalano
- School of Human Health Sciences, University of Florence, 50134 Florence, Italy
| | - Sonia Shabani
- School of Human Health Sciences, University of Florence, 50134 Florence, Italy
| | - Jacopo Venturini
- School of Human Health Sciences, University of Florence, 50134 Florence, Italy
| | - Carlotta Ottanelli
- School of Human Health Sciences, University of Florence, 50134 Florence, Italy
| | - Luca Voltolini
- Thoraco-Pulmonary Surgery Unit, Careggi University Hospital, 50134 Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Giandomenico Roviello
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
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Nie J, Yang R, Zhou R, Deng Y, Li D, Gou D, Zhang Y. Circular RNA circFARSA promotes the tumorigenesis of non-small cell lung cancer by elevating B7H3 via sponging miR-15a-5p. Cell Cycle 2022; 21:2575-2589. [PMID: 35920698 PMCID: PMC9704387 DOI: 10.1080/15384101.2022.2105087] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is currently one of the malignant tumors with the highest incidence and mortality rate in China. Circular RNA hsa_circ_0000896 (circFARSA) has been reported as being an oncogene and a potential biomarker for NSCL. However, the functional role and action mechanism of circFARSA in NSCLC progression have not been fully elucidated. The present study demonstrated that circFRASA was upregulated in NSCLC tissues and cell lines, and its expression was positively correlated with poor prognosis of patients with NSCLC. Further experiments revealed that circFARSA knockdown inhibited cell proliferation, migration, and invasion in vitro experiments, but overexpression of circFARSA exhibited opposite results. Mechanistically, circFARSA facilitated the malignant phenotype of NSCLC cells by enhancing B7H3 expression through sponging miR-15a-5p. In vivo experiments, knockdown of circFARSA restricted tumor growth and metastasis. In conclusion, circFARSA served as a sponge of miR-15a-5p to promote tumorigenesis and development of NSCLC by upregulation of B7H3 expression, which provided evidence of circFARSA maybe act as a novel therapeutic target for NSCLC.
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Affiliation(s)
- Ji Nie
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Ruian Yang
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Ran Zhou
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Yi Deng
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Dengyuan Li
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Deming Gou
- Vascular Disease Research Center, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China,Deming Gou Vascular Disease Research Center, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518060, Guangdong, China
| | - Yunhui Zhang
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China,CONTACT Yunhui Zhang Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province. The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Xishan District, Kunming, 650032, China
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Hont AB, Dumont B, Sutton KS, Anderson J, Kentsis A, Drost J, Hong AL, Verschuur A. The tumor microenvironment and immune targeting therapy in pediatric renal tumors. Pediatr Blood Cancer 2022; 70 Suppl 2:e30110. [PMID: 36451260 DOI: 10.1002/pbc.30110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 12/04/2022]
Abstract
This review highlights the role of several immunomodulating elements contributing to the tumor microenvironment of various pediatric renal tumors including Wilms tumor. The roles of innate and adaptive immune cells in renal tumors are summarized as well as immunomodulatory cytokines and other proteins. The expression and the predictive role of checkpoint modulators like PD-L1 and immunomodulating proteins like glypican-3, B7-H3, COX-2 are highlighted with a translational view toward potential therapeutic innovations. We further discuss the current state of preclinical models in advancing this field of study. Finally, examples of clinical trials of immunomodulating strategies such as monoclonal antibodies and chimeric antigen receptor T (CAR-T) cells for relapsed/refractory/progressive pediatric renal tumors are described.
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Affiliation(s)
- Amy B Hont
- Department of Hematology/Oncology, Children's National Hospital, George Washington University, Washington, District of Columbia, USA
| | - Benoit Dumont
- Pediatric Hematology and Oncology Institute, Léon Bérard Cancer Center, Lyon, France
| | - Kathryn S Sutton
- Department of Pediatrics, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia, USA
| | - John Anderson
- Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Alex Kentsis
- Tow Center for Developmental Oncology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, New York, USA
| | - Jarno Drost
- Princess Máxima Center and Oncode Institute, Utrecht, The Netherlands
| | - Andrew L Hong
- Department of Pediatrics, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia, USA
| | - Arnauld Verschuur
- Department of Pediatric Hematology and Oncology, Hôpital d'Enfants de la Timone, APHM, Marseille, France
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Zhou S, Szöllősi AG, Huang X, Chang-Chien YC, Hajdu A. A Novel Immune-Related Gene Prognostic Index (IRGPI) in Pancreatic Adenocarcinoma (PAAD) and Its Implications in the Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14225652. [PMID: 36428747 PMCID: PMC9688924 DOI: 10.3390/cancers14225652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 10/04/2022] [Accepted: 11/03/2022] [Indexed: 11/19/2022] Open
Abstract
PURPOSE Pancreatic adenocarcinoma (PAAD) is one of the most lethal malignancies, with less than 10% of patients surviving more than 5 years. Existing biomarkers for reliable survival rate prediction need to be enhanced. As a result, the objective of this study was to create a novel immune-related gene prognostic index (IRGPI) for estimating overall survival (OS) and to analyze the molecular subtypes based on this index. Materials and procedures: RNA sequencing and clinical data were retrieved from publicly available sources and analyzed using several R software packages. A unique IRGPI and optimum risk model were developed using a machine learning algorithm. The prediction capability of our model was then compared to that of previously proposed models. A correlation study was also conducted between the immunological tumor microenvironment, risk groups, and IRGPI genes. Furthermore, we classified PAAD into different molecular subtypes based on the expression of IRGPI genes and investigated their features in tumor immunology using the K-means clustering technique. RESULTS A 12-gene IRGPI (FYN, MET, LRSAM1, PSPN, ERAP2, S100A1, IL20RB, MAP3K14, SEMA6C, PRKCG, CXCL11, and GH1) was established, and verified along with a risk model. OS prediction by our model outperformed previous gene signatures. According to the findings of our correlation studies, different risk groups and IRGPI genes were found to be tightly related to tumor microenvironments, and PAAD could be further subdivided into immunologically distinct molecular subtypes based on the expression of IRGPI genes. CONCLUSION The current study constructed and verified a unique IRGPI. Furthermore, our findings revealed a connection between the IRGPI and the immunological microenvironment of tumors. PAAD was differentiated into several molecular subtypes that might react differently to immunotherapy. These findings could provide new insights for precision and translational medicine for more innovative immunotherapy strategies.
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Affiliation(s)
- Shujing Zhou
- Department Data Science and Visualization, Faculty of Informatics, University of Debrecen, 4028 Debrecen, Hungary
- Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Attila Gábor Szöllősi
- Department of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Xufeng Huang
- Department Data Science and Visualization, Faculty of Informatics, University of Debrecen, 4028 Debrecen, Hungary
- Faculty of Dentistry, University of Debrecen, 4032 Debrecen, Hungary
| | - Yi-Che Chang-Chien
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- Correspondence: (Y.-C.C.-C.); (A.H.)
| | - András Hajdu
- Department Data Science and Visualization, Faculty of Informatics, University of Debrecen, 4028 Debrecen, Hungary
- Correspondence: (Y.-C.C.-C.); (A.H.)
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27
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Wilcox JA, Li MJ, Boire AA. Leptomeningeal Metastases: New Opportunities in the Modern Era. Neurotherapeutics 2022; 19:1782-1798. [PMID: 35790709 PMCID: PMC9723010 DOI: 10.1007/s13311-022-01261-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2022] [Indexed: 02/07/2023] Open
Abstract
Leptomeningeal metastases arise from cancer cell entry into the subarachnoid space, inflicting significant neurologic morbidity and mortality across a wide range of malignancies. The modern era of cancer therapeutics has seen an explosion of molecular-targeting agents and immune-mediated strategies for patients with breast, lung, and melanoma malignancies, with meaningful extracranial disease control and improvement in patient survival. However, the clinical efficacy of these agents in those with leptomeningeal metastases remains understudied, due to the relative rarity of this patient population, the investigational challenges associated with studying this dynamic disease state, and brisk disease pace. Nevertheless, retrospective studies, post hoc analyses, and small prospective trials in the last two decades provide a glimmer of hope for patients with leptomeningeal metastases, suggesting that several cancer-directed strategies are not only active in the intrathecal space but also improve survival against historical odds. The continued development of clinical trials devoted to patients with leptomeningeal metastases is critical to establish robust efficacy outcomes in this patient population, define drug pharmacokinetics in the intrathecal space, and uncover new avenues for treatment in the face of leptomeningeal therapeutic resistance.
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Affiliation(s)
- Jessica A Wilcox
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Min Jun Li
- Brain Tumor Center, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Adrienne A Boire
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Brain Tumor Center, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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28
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Li QL, Mao J, Meng XY. Comprehensive Characterization of Immune Landscape Based on Tumor Microenvironment for Oral Squamous Cell Carcinoma Prognosis. Vaccines (Basel) 2022; 10:vaccines10091521. [PMID: 36146599 PMCID: PMC9505673 DOI: 10.3390/vaccines10091521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/05/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Objective: This study aims to identify an immune-related signature to predict clinical outcomes of oral squamous cell carcinoma (OSCC) patients. Methods: Gene transcriptome data of both tumor and normal tissues from OSCC and the corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA). Tumor Immune Estimation Resource algorithm (ESTIMATE) was used to calculate the immune/stromal-related scores. The immune/stromal scores and associated clinical characteristics of OSCC patients were evaluated. Univariate Cox proportional hazards regression analyses, least absolute shrinkage, and selection operator (LASSO) and receiver operating characteristic (ROC) curve analyses were performed to assess the prognostic prediction capacity. Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) function annotation were used to analysis the functions of TME-related genes. Results: Eleven predictor genes were identified in the immune-related signature and overall survival (OS) in the high-risk group was significantly shorter than in the low-risk group. An ROC analysis showed the TME-related signature could predict the total OS of OSCC patients. Moreover, GSEA and GO function annotation proved that immunity and immune-related pathways were mainly enriched in the high-risk group. Conclusions: We identified an immune-related signature that was closely correlated with the prognosis and immune response of OSCC patients. This signature may have important implications for improving the clinical survival rate of OSCC patients and provide a potential strategy for cancer immunotherapy.
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Affiliation(s)
- Qi-Lin Li
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430030, China
| | - Jing Mao
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430030, China
| | - Xin-Yao Meng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Correspondence:
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29
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Lecoq I, Kopp KL, Chapellier M, Mantas P, Martinenaite E, Perez-Penco M, Rønn Olsen L, Zocca MB, Wakatsuki Pedersen A, Andersen MH. CCL22-based peptide vaccines induce anti-cancer immunity by modulating tumor microenvironment. Oncoimmunology 2022; 11:2115655. [PMID: 36052217 PMCID: PMC9427044 DOI: 10.1080/2162402x.2022.2115655] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
CCL22 is a macrophage-derived immunosuppressive chemokine that recruits regulatory T cells through the CCL22:CCR4 axis. CCL22 was shown to play a key role in suppressing anti-cancer immune responses in different cancer types. Recently, we showed that CCL22-specific T cells generated from cancer patients could kill CCL22-expressing tumor cells and directly influence the levels of CCL22 in vitro. The present study aimed to provide a rationale for developing a CCL22-targeting immunotherapy. Vaccination with CCL22-derived peptides induced CCL22-specific T-cell responses in both BALB/c and C57BL/6 mice, assessed by interferon-γ secretion ex vivo. Anti-tumor efficacy of the peptides was evaluated in mouse models engrafted with syngeneic tumor models showing a reduced tumor growth and prolonged survival of the treated mice. Vaccination induced changes in the cellular composition of immune cells that infiltrated the tumor microenvironment assessed with multicolor flow cytometry. In particular, the infiltration of CD8+ cells and M1 macrophages increased, which increased the CD8/Treg and the M1/M2 macrophage ratio. This study provided preclinical evidence that targeting CCL22 with CCL22 peptide vaccines modulated the immune milieu in the tumor microenvironment. This modulation led to an augmentation of anti-tumor responses. This study provided a rationale for developing a novel immunotherapeutic modality in cancer.
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Affiliation(s)
- Inés Lecoq
- Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark.,National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Katharina L Kopp
- Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark
| | - Marion Chapellier
- Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark
| | - Panagiotis Mantas
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Evelina Martinenaite
- Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark.,National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Maria Perez-Penco
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Lars Rønn Olsen
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Mai-Britt Zocca
- Department of Research and Development, IO Biotech ApS, Copenhagen, Denmark
| | | | - Mads Hald Andersen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.,Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
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To kill a cancer: Targeting the immune inhibitory checkpoint molecule, B7-H3. Biochim Biophys Acta Rev Cancer 2022; 1877:188783. [PMID: 36028149 DOI: 10.1016/j.bbcan.2022.188783] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/30/2022] [Accepted: 08/19/2022] [Indexed: 12/26/2022]
Abstract
Targeting the anti-tumor immune response via the B7 family of immune-regulatory checkpoint proteins has revolutionized cancer treatment and resulted in punctuated responses in patients. B7-H3 has gained recent attention given its prominent deregulation and immunomodulatory role in a multitude of cancers. Numerous cancer studies have firmly established a strong link between deregulated B7-H3 expression and poorer outcomes. B7-H3 has been shown to augment cancer cell survival, proliferation, metastasis, and drug resistance by inducing an immune evasive phenotype through its effects on tumor-infiltrating immune cells, cancer cells, cancer-associated vasculature, and the stroma. Given the complex interplay between each of these components of the tumor microenvironment, a deeper understanding of B7-H3 signaling properties is inherently crucial to developing efficacious therapies that can target and inhibit these cancer-promoting interactions. This review delves into the various ways B7-H3 acts as an immunomodulator to facilitate immune evasion and promote tumor growth and spread. With post-transcriptional and post-translational modifications giving rise to different active isoforms coupled with recent discoveries of its putative receptors, B7-H3 can perform diverse functions. Here, we first discuss the dual co-stimulatory/co-inhibitory functions of B7-H3 in the context of normal physiology and cancer. We then discuss the crosstalk facilitated by B7-H3 between stromal components and tumor cells that promote tumor growth and metastasis in different populations of tumor cells, associated vasculature, and the stroma. Concurrently, we highlight therapeutic strategies that can exploit these interactions and their associated limitations, concluding with a special focus on the promise of next-gen in silico-based approaches to small molecule inhibitor drug discovery for B7-H3 that may mitigate these limitations.
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31
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Hu G, Li G, Wen W, Ding W, Zhou Z, Zheng Y, Huang T, Ren J, Chen R, Zhu D, He R, Liang Y, Luo M. Case report: B7-H3 CAR-T therapy partially controls tumor growth in a basal cell carcinoma patient. Front Oncol 2022; 12:956593. [PMID: 36059640 PMCID: PMC9428555 DOI: 10.3389/fonc.2022.956593] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
B7-H3 is over-expressed in multiple types of solid tumors, making it an ideal target for chimeric antigen receptor (CAR)-T therapy. Here, we first report a case of multiple basal cell carcinoma (BCC) patient treated with humanized monoclonal anti-B7-H3 CAR-T cells through direct intratumoral injection. After three dose-escalated injections, the lesion in the abdomen decreased by 40% in volume, shrank from bulging to flat, but was not eradicated completely. The large lesion in the forehead became dry from original ulcer and bleeding. The adverse events observed were itching, myalgia, and redness. Immunohistochemistry analysis demonstrated that B7-H3-positive tumor cells and B7-H3 expression intensity were reduced after injections of CAR-T cells. The number of infiltrating CD3 T cells increased significantly but mainly located outside the tumor region. Subsequently, high levels of TGF-β in the tumor area were observed, suggesting that solid tumor microenvironment may hinder the infiltration and effect of CAR-T cells. In summary, in this particular case report, intratumoral injection of B7-H3 CAR-T cells partially controls tumor growth in the BCC patient with minor adverse events. The efficacy and safety of B7-H3 CAR-T therapy need to be further investigated with a larger cohort of patients. Although only one clinical case is reported here, the anti-B7-H3 CAR-T cell therapy should be considered as a treatment option for solid tumors in the future. This clinical trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) with registration number ChiCTR2100044386.
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Affiliation(s)
- Gang Hu
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Gang Hu, ; Yunsheng Liang, ; Min Luo,
| | - Guangchao Li
- Research and Development Department Guangzhou Bio-Gene Technology Co., Ltd., Guangzhou, China
| | - Wei Wen
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Wen Ding
- Research and Development Department Guangzhou Bio-Gene Technology Co., Ltd., Guangzhou, China
| | - Zhao Zhou
- Research and Development Department Guangzhou Bio-Gene Technology Co., Ltd., Guangzhou, China
| | - Yongwei Zheng
- Research and Development Department Guangzhou Bio-Gene Technology Co., Ltd., Guangzhou, China
| | - Taoyuan Huang
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Junnan Ren
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Rongyi Chen
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Dingheng Zhu
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Renliang He
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Yunsheng Liang
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Gang Hu, ; Yunsheng Liang, ; Min Luo,
| | - Min Luo
- Research and Development Department Guangzhou Bio-Gene Technology Co., Ltd., Guangzhou, China
- *Correspondence: Gang Hu, ; Yunsheng Liang, ; Min Luo,
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Abstract
Since B7-H3 is overexpressed or amplified in many types of solid tumors with a restricted expression in the normal tissues, it has been an emerging immunotherapeutic target for solid tumors. This review will focus on the structural designs of developing chimeric antigen receptors (CARs) targeting B7-H3. The expression, receptor, and function of the B7-H3, as well as a short overview of B7-H3-targeted monoclonal antibody therapy, are discussed. Finally, a detailed summary of B7-H3 redirected CAR-T and CAR-NK cell approaches utilized in preclinical models and currently ongoing or completed clinical trials are presented. It has been demonstrated that B7-H3-targeted CAR-based cell therapies were safe in initial trials, but their efficacy was limited. Employing the local delivery routes, the introduction of novel modifications promoting CAR-T persistence, and combined treatment with other standard therapies could improve the efficacy of B7-H3-targeted CAR-T cell therapy against solid tumors.
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Affiliation(s)
- Guangfei Li
- ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Haopeng Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Haitao Wu
- ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Jian Chen
- ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China
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Origin and Therapies of Osteosarcoma. Cancers (Basel) 2022; 14:cancers14143503. [PMID: 35884563 PMCID: PMC9322921 DOI: 10.3390/cancers14143503] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 01/15/2023] Open
Abstract
Simple Summary Osteosarcoma is the most common malignant bone tumor in children, with a 5-year survival rate ranging from 70% to 20% depending on the aggressiveness of the disease. The current treatments have not evolved over the past four decades due in part to the genetic complexity of the disease and its heterogeneity. This review will summarize the current knowledge of OS origin, diagnosis and therapies. Abstract Osteosarcoma (OS) is the most frequent primary bone tumor, mainly affecting children and young adults. Despite therapeutic advances, the 5-year survival rate is 70% but drastically decreases to 20–30% for poor responders to therapies or for patients with metastasis. No real evolution of the survival rates has been observed for four decades, explained by poor knowledge of the origin, difficulties related to diagnosis and the lack of targeted therapies for this pediatric tumor. This review will describe a non-exhaustive overview of osteosarcoma disease from a clinical and biological point of view, describing the origin, diagnosis and therapies.
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Pathania AS, Prathipati P, Murakonda SP, Murakonda AB, Srivastava A, Avadhesh A, Byrareddy SN, Coulter DW, Gupta SC, Challagundla KB. Immune checkpoint molecules in neuroblastoma: A clinical perspective. Semin Cancer Biol 2022; 86:247-258. [PMID: 35787940 DOI: 10.1016/j.semcancer.2022.06.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 06/21/2022] [Accepted: 06/28/2022] [Indexed: 10/31/2022]
Abstract
High-risk neuroblastoma (NB) is challenging to treat with 5-year long-term survival in patients remaining below 50% and low chances of survival after tumor relapse or recurrence. Different strategies are being tested or under evaluation to destroy resistant tumors and improve survival outcomes in NB patients. Immunotherapy, which uses certain parts of a person's immune system to recognize or kill tumor cells, effectively improves patient outcomes in several types of cancer, including NB. One of the immunotherapy strategies is to block immune checkpoint signaling in tumors to increase tumor immunogenicity and anti-tumor immunity. Immune checkpoint proteins put brakes on immune cell functions to regulate immune activation, but this activity is exploited in tumors to evade immune surveillance and attack. Immune checkpoint proteins play an essential role in NB biology and immune escape mechanisms, which makes these tumors immunologically cold. Therapeutic strategies to block immune checkpoint signaling have shown promising outcomes in NB but only in a subset of patients. However, combining immune checkpoint blockade with other therapies, including conjugated antibody-based immunotherapy, radioimmunotherapy, tumor vaccines, or cellular therapies like modified T or natural killer (NK) cells, has shown encouraging results in enhancing anti-tumor immunity in the preclinical setting. An analysis of publicly available dataset using computational tools has unraveled the complexity of multiple cancer including NB. This review comprehensively summarizes the current information on immune checkpoint molecules, their biology, role in immune suppression and tumor development, and novel therapeutic approaches combining immune checkpoint inhibitors with other therapies to combat high-risk NB.
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Affiliation(s)
- Anup S Pathania
- Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Philip Prathipati
- Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki City, Osaka 567-0085, Japan
| | - Swati P Murakonda
- Sri Rajiv Gandhi College of Dental Sciences & Hospital, Bengaluru, Karnataka 560032, India
| | - Ajay B Murakonda
- Sree Sai Dental College & Research Institute, Srikakulam, Andhra Pradesh 532001, India
| | - Ankit Srivastava
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India
| | - Avadhesh Avadhesh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Don W Coulter
- Department of Pediatrics, Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Subash C Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India; Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, Assam, India.
| | - Kishore B Challagundla
- Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; The Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Donlon NE, Davern M, O’Connell F, Sheppard A, Heeran A, Bhardwaj A, Butler C, Narayanasamy R, Donohoe C, Phelan JJ, Lynam-Lennon N, Dunne MR, Maher S, O’Sullivan J, Reynolds JV, Lysaght J. Impact of radiotherapy on the immune landscape in oesophageal adenocarcinoma. World J Gastroenterol 2022; 28:2302-2319. [PMID: 35800186 PMCID: PMC9185220 DOI: 10.3748/wjg.v28.i21.2302] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/19/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In the contemporary era of cancer immunotherapy, an abundance of clinical and translational studies have reported radiotherapy (RT) and immunotherapies as a viable option for immunomodulation of many cancer subtypes, with many related clinical trials ongoing. In locally advanced disease, chemotherapy or chemoradiotherapy followed by surgical excision of the tumour remain the principal treatment strategy in oesophageal adenocarcinoma (OAC), however, the use of the host immune system to improve anti-tumour immunity is rapidly garnering increased support in the curative setting.
AIM To immunophenotype OAC patients’ immune checkpoint (IC) expression with and without radiation and evaluate the effects of checkpoint blockade on cell viability.
METHODS In the contemporary era of cancer immunotherapy, an abundance of studies have demonstrated that combination RT and IC inhibitors (ICIs) are effective in the immunomodulation of many cancer subtypes, with many related clinical trials ongoing. Although surgical excision and elimination of tumour cells by chemotherapy or chemoradiotherapy remains the gold standard approach in OAC, the propagation of anti-tumour immune responses is rapidly garnering increased support in the curative setting. The aim of this body of work was to immunophenotype OAC patients’ IC expression with and without radiation and to establish the impact of checkpoint blockade on cell viability. This study was a hybrid combination of in vitro and ex vivo models. Quantification of serum immune proteins was performed by enzyme-linked immunosorbent assay. Flow cytometry staining was performed to evaluate IC expression for in vitro OAC cell lines and ex vivo OAC biopsies. Cell viability in the presence of radiation with and without IC blockade was assessed by a cell counting kit-8 assay.
RESULTS We identified that conventional dosing and hypofractionated approaches resulted in increased IC expression (PD-1, PD-L1, TIM3, TIGIT) in vitro and ex vivo in OAC. There were two distinct subcohorts with one demonstrating significant upregulation of ICs and the contrary in the other cohort. Increasing IC expression post RT was associated with a more aggressive tumour phenotype and adverse features of tumour biology. The use of anti-PD-1 and anti-PD-L1 immunotherapies in combination with radiation resulted in a significant and synergistic reduction in viability of both radiosensitive and radioresistant OAC cells in vitro. Interleukin-21 (IL-21) and IL-31 significantly increased, with a concomitant reduction in IL-23 as a consequence of 4 Gray radiation. Similarly, radiation induced an anti-angiogenic tumour milieu with reduced expression of vascular endothelial growth factor-A, basic fibroblast growth factor, Flt-1 and placental growth factor.
CONCLUSION The findings of the current study demonstrate synergistic potential for the use of ICIs and ionising radiation to potentiate established anti-tumour responses in the neoadjuvant setting and is of particular interest in those with advanced disease, adverse features of tumour biology and poor treatment responses to conventional therapies.
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Affiliation(s)
- Noel E Donlon
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Maria Davern
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Fiona O’Connell
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Andrew Sheppard
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Aisling Heeran
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Anshul Bhardwaj
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Christine Butler
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Ravi Narayanasamy
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Claire Donohoe
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - James J Phelan
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Margaret R Dunne
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Stephen Maher
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Jacintha O’Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - John V Reynolds
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Joanne Lysaght
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
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Zhang S, Black RG, Kohli K, Hayes BJ, Miller C, Koehne A, Schroeder BA, Abrams K, Schulte BC, Alexiev BA, Heimberger AB, Zhang A, Jing W, Ng JCK, Shinglot H, Seguin B, Salter AI, Riddell SR, Jensen MC, Gottschalk S, Moore PF, Torok-Storb B, Pollack SM. B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model. Mol Cancer Ther 2022; 21:999-1009. [PMID: 35405743 PMCID: PMC9381119 DOI: 10.1158/1535-7163.mct-21-0726] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 01/31/2022] [Accepted: 03/31/2022] [Indexed: 01/07/2023]
Abstract
One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3-specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.
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Affiliation(s)
- Shihong Zhang
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - R. Graeme Black
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Karan Kohli
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Brian J. Hayes
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Cassandra Miller
- Comparative Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Amanda Koehne
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Brett A. Schroeder
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,NCI, NIH, Bethesda, Maryland
| | - Kraig Abrams
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Brian C. Schulte
- Department of Medicine, University of California San Francisco, San Francisco, California
| | | | - Amy B. Heimberger
- Department of Neurologic Surgery, Northwestern University, Chicago, Illinois
| | - Ali Zhang
- Department of Medicine, Northwestern University, Chicago, Illinois
| | - Weiqing Jing
- Department of Medicine, Northwestern University, Chicago, Illinois
| | | | - Himaly Shinglot
- Department of Medicine, Northwestern University, Chicago, Illinois
| | - Bernard Seguin
- Colorado State University, Flint Animal Cancer Center, Fort Collins, Colorado
| | - Alexander I. Salter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Stanley R. Riddell
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Lyell Immunopharma, Seattle, Washington
| | - Michael C. Jensen
- Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington
| | - Stephen Gottschalk
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Peter F. Moore
- Department of Veterinary Medicine, University of California Davis, Davis, California
| | - Beverly Torok-Storb
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Seth M. Pollack
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Medicine, Northwestern University, Chicago, Illinois.,Corresponding Author: Seth M. Pollack, Oncology, Northwestern University, 303 E. Superior St. #3-115, Chicago, IL 60611. E-mail:
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Harland N, Maurer FB, Abruzzese T, Bock C, Montes-Mojarro IA, Fend F, Aicher WK, Stenzl A, Amend B. Elevated Expression of the Immune Checkpoint Ligand CD276 (B7-H3) in Urothelial Carcinoma Cell Lines Correlates Negatively with the Cell Proliferation. Int J Mol Sci 2022; 23:4969. [PMID: 35563359 PMCID: PMC9100984 DOI: 10.3390/ijms23094969] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/22/2022] [Accepted: 04/26/2022] [Indexed: 12/15/2022] Open
Abstract
The cell surface molecule CD276 (B7-H3) is an immune checkpoint antigen. The elevated expression of CD276 on tumors contributes to the suppression of anti-tumor T-cell responses and correlates with poor prognosis. METHODS The expression of CD276 was explored in vitro on eight urothelial carcinoma cell lines (UM-UC) in comparison to eight normal urothelial cells (NUCs) by RT-qPCR, Western blotting, and flow cytometry. Cell proliferation was enumerated over consecutive passages. The expression of cancer stem cell markers CD24 and CD44, cytokeratins, and vimentin was investigated by immunofluorescence. The expression of CD276 in bladder tumor samples and metastases was explored by immunohistochemistry. RESULTS Expression of CD276 on cell surfaces was elevated on UM-UCs when compared to NUCs. In UM-UCs, CD276 transcripts correlated moderately positive with CD276 protein expression (ρ = 0.660) and strongly positive with CD276 surface-expression (ρ = 0.810). CD276 mRNA expression (ρ = -0.475) and CD276 protein expression (ρ = -0.417) had a significant negative correlation with proliferation, while a significant correlation between proliferation and cell surface expression was not observed in UM-UCs. CONCLUSION The expression of CD276 on UM-UC bladder tumor cell surfaces is elevated. Slow proliferating UM-UC cells express more CD276 mRNA and protein than fast proliferating cells. In patients, slow proliferating CD276high tumor (stem) cells may evade immune surveillance. However, cancer therapy targeting CD276 may be effective in the treatment of slow proliferating tumor cells.
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Affiliation(s)
- Niklas Harland
- Department of Urology, University of Tuebingen Hospital, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany; (N.H.); (A.S.)
| | - Florian B. Maurer
- Center for Medical Research, University of Tuebingen Hospital, Waldhoernlestr. 22, 72072 Tuebingen, Germany; (F.B.M.); (T.A.); (C.B.); (W.K.A.)
| | - Tanja Abruzzese
- Center for Medical Research, University of Tuebingen Hospital, Waldhoernlestr. 22, 72072 Tuebingen, Germany; (F.B.M.); (T.A.); (C.B.); (W.K.A.)
| | - Cornelia Bock
- Center for Medical Research, University of Tuebingen Hospital, Waldhoernlestr. 22, 72072 Tuebingen, Germany; (F.B.M.); (T.A.); (C.B.); (W.K.A.)
| | - Ivonne A. Montes-Mojarro
- Institute for Pathology, Eberhard-Karls-University, 72072 Tuebingen, Germany; (I.A.M.-M.); (F.F.)
| | - Falko Fend
- Institute for Pathology, Eberhard-Karls-University, 72072 Tuebingen, Germany; (I.A.M.-M.); (F.F.)
| | - Wilhelm K. Aicher
- Center for Medical Research, University of Tuebingen Hospital, Waldhoernlestr. 22, 72072 Tuebingen, Germany; (F.B.M.); (T.A.); (C.B.); (W.K.A.)
| | - Arnulf Stenzl
- Department of Urology, University of Tuebingen Hospital, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany; (N.H.); (A.S.)
| | - Bastian Amend
- Department of Urology, University of Tuebingen Hospital, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany; (N.H.); (A.S.)
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Donlon NE, Davern M, Sheppard AD, O'Connell F, Dunne MR, Hayes C, Mylod E, Ramjit S, Temperley H, Mac Lean M, Cotter G, Bhardwaj A, Butler C, Conroy MJ, O'Sullivan J, Ravi N, Donohoe CL, Reynolds JV, Lysaght J. The Impact of Esophageal Oncological Surgery on Perioperative Immune Function; Implications for Adjuvant Immune Checkpoint Inhibition. Front Immunol 2022; 13:823225. [PMID: 35154142 PMCID: PMC8829578 DOI: 10.3389/fimmu.2022.823225] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/10/2022] [Indexed: 11/17/2022] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) are being investigated for their role as an adjunct in the multimodal treatment of esophageal adenocarcinoma (EAC). The most effective time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumor immunity perioperatively to help inform the optimal timing of ICIs into current standards of care for EAC patients. Methods Systemic immunity in 11 EAC patients was phenotyped immediately prior to esophagectomy (POD-0) and post-operatively (POD)-1, 3, 7 and week 6. Longitudinal serological profiling was conducted by ELISA. The frequency of circulating lymphocytes, activation status, immune checkpoint expression and damage-associated molecular patterns was assessed by flow cytometry. Results The frequency of naïve T-cells significantly increased in circulation post-esophagectomy from POD-0 to POD-7 (p<0.01) with a significant decrease in effector memory T-cells by POD7 followed by a subsequent increase by week 6 (p<0.05). A significant increase in activated circulating CD27+ T-cells was observed from POD-0 to POD-7 (p<0.05). The percentage of PD-1+ and CTLA-4+ T-cells peaked on POD-1 and was significantly decreased by week 6 (p<0.01). There was a significant increase in soluble PD-1, PD-L2, TIGIT and LAG-3 from POD-3 to week 6 (p<0.01). Increased checkpoint expression correlated with those who developed metastatic disease early in their postoperative course. Th1 cytokines and co-stimulatory factors decreased significantly in the immediate post-operative setting, with a reduction in IFN-γ, IL-12p40, IL-1RA, CD28, CD40L and TNF-α. A simultaneous increase was observed in Th2 cytokines in the immediate post-operative setting, with a significant increase in IL-4, IL-10, IL-16 and MCP-1 before returning to preoperative levels at week 6. Conclusion Our study highlights the prevailing Th2-like immunophenotype post-surgery. Therefore, shifting the balance in favour of a Th1-like phenotype would offer a potent therapeutic approach to promote cancer regression and prevent recurrence in the adjuvant setting and could potentially propagate anti-tumour immune responses perioperatively if administered in the immediate neoadjuvant setting. Consequently, this body of work paves the way for further studies and appropriate trial design is needed to further interrogate and validate the use of ICI in the multimodal treatment of locally advanced disease in the neoadjuvant and adjuvant setting.
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Affiliation(s)
- Noel E Donlon
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.,Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Maria Davern
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.,Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Andrew D Sheppard
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.,Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Fiona O'Connell
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Margaret R Dunne
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Conall Hayes
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Eimear Mylod
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.,Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Sinead Ramjit
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Hugo Temperley
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Michael Mac Lean
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Gillian Cotter
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Anshul Bhardwaj
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Christine Butler
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Melissa J Conroy
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.,Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Jacintha O'Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Narayanasamy Ravi
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Claire L Donohoe
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - John V Reynolds
- Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Joanne Lysaght
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, St James's Hospital, Dublin, Ireland.,Department of Surgery, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute Trinity College Dublin, St James's Hospital, Dublin, Ireland
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Xia C, Huang W, Chen YL, Fu HB, Tang M, Zhang TL, Li J, Lv GH, Yan YG, Ouyang ZH, Yao N, Wang C, Zou MX. Coexpression of HHLA2 and PD-L1 on Tumor Cells Independently Predicts the Survival of Spinal Chordoma Patients. Front Immunol 2022; 12:797407. [PMID: 35145510 PMCID: PMC8824251 DOI: 10.3389/fimmu.2021.797407] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/31/2021] [Indexed: 12/19/2022] Open
Abstract
Background Immunotherapy only achieves efficacy in some cancer patients, and less is known about other immune checkpoint molecules in chordoma. Here, we aimed to determine the expression of PD-L1, HHLA2, B7H3, IDO-1 and Galectin-9 in spinal chordoma and evaluated their association with tumor infiltrating lymphocytes (TILs), clinicopathological characteristics and survival of patients. Methods Using multiplexed quantitative immunofluorescence (QIF), we simultaneously measured the levels of five different immune checkpoint molecules and major TIL subsets in 92 human spinal chordoma samples. Results Tumor HHLA2 and PD-L1 were positive in 80.0% and 86.0% of cases, respectively. However, B7H3, IDO-1 and Galectin-9 positivity on tumor cells were only seen in 21.0% of cases, despite all showing predominantly stromal expression. Coexpression of these QIF markers in the tumor compartment was scarcely detected except for PD-L1 and HHLA2, which was observed in 69.6% of cases. While tumoral HHLA2 and stromal B7H3 expressions were associated with an aggressive tumor phenotype, suppressive immune response (specifically including elevated PD-1+ TILs level and decreased CD8+ TIL density) and poor prognosis, stromal levels of PD-L1 and Galectin-9 predicted the opposite outcomes. Importantly, HHLA2 and PD-L1 coexpression on tumor cells independently predicted both worse local recurrence-free survival and overall survival. Conclusion These data provide a better understanding of the immunosuppressive mechanism in chordoma and may be useful for the development of combination or novel immunotherapy approaches aiming to improve therapeutic efficacy and survival.
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Affiliation(s)
- Chao Xia
- The First Affiliated Hospital, Health Management Center, Hengyang Medical School, University of South China, Hengyang, China.,Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Wei Huang
- The First Affiliated Hospital, Health Management Center, Hengyang Medical School, University of South China, Hengyang, China
| | - Yun-Liang Chen
- Shenzhen Audaque Data Technology Co., Ltd., Shenzhen, China
| | - Hai-Bin Fu
- Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Ming Tang
- Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Tao-Lan Zhang
- Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Jing Li
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Guo-Hua Lv
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yi-Guo Yan
- Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Zhi-Hua Ouyang
- Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Nvzhao Yao
- Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Cheng Wang
- Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Ming-Xiang Zou
- Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
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40
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Tarone L, Giacobino D, Camerino M, Ferrone S, Buracco P, Cavallo F, Riccardo F. Canine Melanoma Immunology and Immunotherapy: Relevance of Translational Research. Front Vet Sci 2022; 9:803093. [PMID: 35224082 PMCID: PMC8873926 DOI: 10.3389/fvets.2022.803093] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/10/2022] [Indexed: 11/17/2022] Open
Abstract
In veterinary oncology, canine melanoma is still a fatal disease for which innovative and long-lasting curative treatments are urgently required. Considering the similarities between canine and human melanoma and the clinical revolution that immunotherapy has instigated in the treatment of human melanoma patients, special attention must be paid to advancements in tumor immunology research in the veterinary field. Herein, we aim to discuss the most relevant knowledge on the immune landscape of canine melanoma and the most promising immunotherapeutic approaches under investigation. Particular attention will be dedicated to anti-cancer vaccination, and, especially, to the encouraging clinical results that we have obtained with DNA vaccines directed against chondroitin sulfate proteoglycan 4 (CSPG4), which is an appealing tumor-associated antigen with a key oncogenic role in both canine and human melanoma. In parallel with advances in therapeutic options, progress in the identification of easily accessible biomarkers to improve the diagnosis and the prognosis of melanoma should be sought, with circulating small extracellular vesicles emerging as strategically relevant players. Translational advances in melanoma management, whether achieved in the human or veterinary fields, may drive improvements with mutual clinical benefits for both human and canine patients; this is where the strength of comparative oncology lies.
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Affiliation(s)
- Lidia Tarone
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Davide Giacobino
- Department of Veterinary Sciences, University of Turin, Turin, Italy
| | | | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Paolo Buracco
- Department of Veterinary Sciences, University of Turin, Turin, Italy
| | - Federica Cavallo
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Federica Riccardo
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy
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Shi J, Zhao H, Lian H, Ke L, Zhao L, Wang C, Han Q. CD276 (B7H3) improve cancer stem cells formation in cervical carcinoma cell lines. Transl Cancer Res 2022; 10:65-72. [PMID: 35116240 PMCID: PMC8798926 DOI: 10.21037/tcr-19-2910] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 11/20/2020] [Indexed: 12/15/2022]
Abstract
Background Cancer stem cells (CSCs) have been considered as a potential therapeutic target for cervical carcinoma. CD 276 is a well-known immune check point molecular, but its relationship with cervical CSCs was still unclear. Methods HeLa cell lines were obtained as cervical carcinoma in vitro model. HeLa cell Sphere formation culture was performed and CD276, OCT4 and SOX2 expression were determined by RT-qPCR. Transiently transfection and siRNA interference were used to modify CD276 expression. HeLa cell colony has been counted and cell proliferation was assessed by MTT assay. The relationship between CD276 and chemotherapy resistance of HeLa cell were evaluated by cisplatin treatment. Additionally, the mice model of xenograft tumor was established and CD276’s function was evaluated in vivo. Results Here, we demonstrate that the expression of CD276 is positively correlated with the amount of sphere-forming cells in HeLa cell lines. Overexpression of CD276 causes the inhibition of HeLa cells’ sphere formation, colony formation and cell viability. Meanwhile, the downregulation of CD276 leads to the other way. We also demonstrate that CD276 contributes to the chemotherapy resistance in the cell line. Furthermore, we verify the CD276’s function on HeLa xenotransplantation mice model. Conclusions These results suggest that CD276 elevates the self-renewal capacity of HeLa CSCs.
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Affiliation(s)
- Jianfeng Shi
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Haishan Zhao
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Huan Lian
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Linnan Ke
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Lei Zhao
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Chunren Wang
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
| | - Qianqian Han
- Division of Biomaterials, Department of Medical Devices, Chinese National Institutes for Food and Drug Control, Beijing, China
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Ciprut S, Berberich A, Knoll M, Pusch S, Hoffmann D, Furkel J, Ward Gahlawat A, Kahlert-Konzelamnn L, Sahm F, Warnken U, Winter M, Schnölzer M, Pusch S, von Deimling A, Abdollahi A, Wick W, Lemke D. AAMP is a binding partner of costimulatory human B7-H3. Neurooncol Adv 2022; 4:vdac098. [PMID: 35919070 PMCID: PMC9341442 DOI: 10.1093/noajnl/vdac098] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background Targeted immunotherapies are of growing interest in the treatment of various cancers. B7 homolog 3 protein (B7-H3), a member of the co-stimulatory/-inhibitory B7-family, exerts immunosuppressive and pro-tumorigenic functions in various cancer types and is under evaluation in ongoing clinical trials. Unfortunately, interaction partner(s) remain unknown which restricts the druggability. Methods Aiming to identify potential binding partner(s) of B7-H3, a yeast two-hybrid and a mass spectrometry screen were performed. Potential candidates were evaluated by bimolecular fluorescence complementation (BiFC) assay, co-immunoprecipitation (co-IP), and functionally in a 3H-thymidine proliferation assay of Jurkat cells, a T-cell lineage cell line. Prognostic value of angio-associated migratory cell protein (AAMP) and B7-H3 expression was evaluated in isocitrate dehydrogenase 1 wildtype (IDH1wt) glioblastoma (GBM) patients from The Cancer Genome Atlas (TCGA)-GBM cohort. Results Of the screening candidates, CD164, AAMP, PTPRA, and SLAMF7 could be substantiated via BiFC. AAMP binding could be further confirmed via co-IP and on a functional level. AAMP was ubiquitously expressed in glioma cells, immune cells, and glioma tissue, but did not correlate with glioma grade. Finally, an interaction between AAMP and B7-H3 could be observed on expression level, hinting toward a combined synergistic effect. Conclusions AAMP was identified as a novel interaction partner of B7-H3, opening new possibilities to create a targeted therapy against the pro-tumorigenic costimulatory protein B7-H3.
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Affiliation(s)
- Sara Ciprut
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neurology, University of Heidelberg Medical School and National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Anne Berberich
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neurology, University of Heidelberg Medical School and National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Maximilian Knoll
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Consortium (DKTK) Core Center Heidelberg, German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Stefan Pusch
- German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg , Heidelberg , Germany
| | - Dirk Hoffmann
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neurology, University of Heidelberg Medical School and National Center for Tumor Diseases (NCT) , Heidelberg , Germany
- Faculty of Biosciences, Heidelberg University , Heidelberg , Germany
| | - Jennifer Furkel
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Consortium (DKTK) Core Center Heidelberg, German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Aoife Ward Gahlawat
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Consortium (DKTK) Core Center Heidelberg, German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Lena Kahlert-Konzelamnn
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neurology, University of Heidelberg Medical School and National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Felix Sahm
- German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg , Heidelberg , Germany
| | - Uwe Warnken
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neurology, University of Heidelberg Medical School and National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Martin Winter
- Department of Functional Proteome Analysis, German Cancer Research Center (DKFZ) , Heidelberg , Germany
| | - Martina Schnölzer
- Department of Functional Proteome Analysis, German Cancer Research Center (DKFZ) , Heidelberg , Germany
| | - Sonja Pusch
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neurology, University of Heidelberg Medical School and National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Andreas von Deimling
- German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg , Heidelberg , Germany
| | - Amir Abdollahi
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Consortium (DKTK) Core Center Heidelberg, German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Wolfgang Wick
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neurology, University of Heidelberg Medical School and National Center for Tumor Diseases (NCT) , Heidelberg , Germany
| | - Dieter Lemke
- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany
- Department of Neurology, University of Heidelberg Medical School and National Center for Tumor Diseases (NCT) , Heidelberg , Germany
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Lin W, Xu Y, Gao J, Zhang H, Sun Y, Qiu X, Huang Q, Kong L, Lu JJ. Multi-Omics Data Analyses Identify B7-H3 as a Novel Prognostic Biomarker and Predict Response to Immune Checkpoint Blockade in Head and Neck Squamous Cell Carcinoma. Front Immunol 2021; 12:757047. [PMID: 34675936 PMCID: PMC8524082 DOI: 10.3389/fimmu.2021.757047] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/16/2021] [Indexed: 11/24/2022] Open
Abstract
B7 homolog 3 (B7-H3) is a recently found superfamily B7 molecule and therefore has significant involvement in immunological regulation. However, the relationships of B7-H3 expression with the tumor microenvironment (TME), response to immunotherapy, and prognosis in head and neck squamous cell carcinoma (HNSCC) are still unknown. In the present analysis, we determined B7-H3 as a novel biomarker that predicts the prognosis and response to immunotherapy in HNSCC. B7-H3 expression is enhanced in HNSCC compared to normal sample and is stably expressed in HNSCC cell line. Besides, high B7-H3 expression is correlated with a dismal prognosis and resistance to immunotherapy and contributes to an immunosuppressive microenvironment. Moreover, single-cell RNA sequencing (scRNA-seq) analysis shows that B7-H3 is mainly expressed in the stromal as well as malignant cells. In conclusion, the study provides insight in understanding the prognostic value of B7-H3 in HNSCC and highlights its involvement in promoting the immunosuppressive microenvironment, which presents an attractive strategy for antibody-based immunotherapy.
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Affiliation(s)
- Wanzun Lin
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Yanyan Xu
- Department of Gynaecology and Obstetrics, Shanghai Jiangqiao Hospital, Shanghai, China
| | - Jing Gao
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Haojiong Zhang
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Yun Sun
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Xianxin Qiu
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Qingting Huang
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Lin Kong
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Jiade J Lu
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
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Effective killing of cells expressing CD276 (B7-H3) by a bispecific T cell engager based on a new fully human antibody. Transl Oncol 2021; 14:101232. [PMID: 34601396 PMCID: PMC8493583 DOI: 10.1016/j.tranon.2021.101232] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/24/2021] [Indexed: 01/01/2023] Open
Abstract
A new fully human antibody, B11, that specifically targets CD276 was identified. The epitope of B11 is the V1/V2 domain of CD276 and it competes with the antibody 8H9 (Omburtamab). B11-BiTE mediates strong T cell cytotoxicity to 14 different tumor cell lines. The pancaner molecule CD276 (B7-H3) is an attractive target for antibody based therapy. We identified from a large (1011) phage-displayed single-chain variable fragment (scFv) library, a fully human antibody, B11, which bound with high avidity (KD=0.4 nM) to CD276. B11 specifically bound to the V1/V2 domain of CD276 and competed with the antibody 8H9 (Omburtamab). It was used to design an IgG-format bispecific T cell engager B11-BiTE, which was more effective than 8H9-BiTE in 14 different cancer cell lines. B11-BiTE also exhibited strong ADCC/ADCP. Therefore, the fully human B11-BiTE is a promising candidate for treatment of tumors expressing CD276.
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Genomic and Transcriptomic Characterization of Relapsed SCLC Through Rapid Research Autopsy. JTO Clin Res Rep 2021; 2:100164. [PMID: 34590014 PMCID: PMC8474405 DOI: 10.1016/j.jtocrr.2021.100164] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 03/05/2021] [Indexed: 01/22/2023] Open
Abstract
Introduction Relapsed SCLC is characterized by therapeutic resistance and high mortality rate. Despite decades of research, mechanisms responsible for therapeutic resistance have remained elusive owing to limited tissues available for molecular studies. Thus, an unmet need remains for molecular characterization of relapsed SCLC to facilitate development of effective therapies. Methods We performed whole-exome and transcriptome sequencing of metastatic tumor samples procured from research autopsies of five patients with relapsed SCLC. We implemented bioinformatics tools to infer subclonal phylogeny and identify recurrent genomic alterations. We implemented immune cell signature and single-sample gene set enrichment analyses on tumor and normal transcriptome data from autopsy and additional primary and relapsed SCLC data sets. Furthermore, we evaluated T cell-inflamed gene expression profiles in neuroendocrine (ASCL1, NEUROD1) and non-neuroendocrine (YAP1, POU2F3) SCLC subtypes. Results Exome sequencing revealed clonal heterogeneity (intertumor and intratumor) arising from branched evolution and identified resistance-associated truncal and subclonal alterations in relapsed SCLC. Transcriptome analyses further revealed a noninflamed phenotype in neuroendocrine SCLC subtypes (ASCL1, NEUROD1) associated with decreased expression of genes involved in adaptive antitumor immunity whereas non-neuroendocrine subtypes (YAP1, POU2F3) revealed a more inflamed phenotype. Conclusions Our results reveal substantial tumor heterogeneity and complex clonal evolution in relapsed SCLC. Furthermore, we report that neuroendocrine SCLC subtypes are immunologically cold, thus explaining decreased responsiveness to immune checkpoint blockade. These results suggest that the mechanisms of innate and acquired therapeutic resistances are subtype-specific in SCLC and highlight the need for continued investigation to bolster therapy selection and development for this cancer.
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46
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Immune Profiling of Medullary Thyroid Cancer-An Opportunity for Immunotherapy. Genes (Basel) 2021; 12:genes12101534. [PMID: 34680929 PMCID: PMC8536131 DOI: 10.3390/genes12101534] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/24/2021] [Accepted: 09/26/2021] [Indexed: 01/13/2023] Open
Abstract
Medullary thyroid cancer (MTC) is a rare malignancy that arises from calcitonin-producing C-cells. Curative treatment for patients with metastatic MTC is challenging. Identifying the mechanisms by which cancer cells inhibit the activity of immune cells provides an opportunity to develop new therapies that restore anticancer activity. Little is known about the immunological phenomena underlying MTC. Here, we examined the expression profile of 395 genes associated with MTC. The study included 51 patients diagnosed with MTC at a single center. Bioinformatical analysis revealed that CD276 expression in MTC cells was at least three-fold higher than that in normal tissue. The expression of CD276 showed a weak but statistically significant positive correlation with tumor diameter, but we did not find a significant association between CD276 expression and other histopathological clinical factors, or the response to initial therapy. A search of published data identified the monoclonal antibody (inhibitor) enoblituzumab as a potential drug for patients diagnosed with MTC overexpressing CD276.
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Sun H, Li J, Hu W, Yan Y, Guo Z, Zhang Z, Chen Y, Yao X, Teng L, Wang X, Li L, Chai D, Zheng J, Wang G. Co-immunizing with HMGB1 enhances anti-tumor immunity of B7H3 vaccine in renal carcinoma. Mol Immunol 2021; 139:184-192. [PMID: 34560414 DOI: 10.1016/j.molimm.2021.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 08/16/2021] [Accepted: 09/02/2021] [Indexed: 11/27/2022]
Abstract
Metastatic renal carcinoma is a kind of tumor with high degree of malignancy, but there are no effective treatment methods and strategies at present. In this study, we designed a folate-grafted PEI600-CyD (H1) nanoparticle-mediated DNA vaccine containing an adjuvant of high mobility group box 1 protein (HMGB1) and a tumor-specific antigen of B7H3 (CD276) for renal carcinoma therapy. Mice bearing subcutaneous human B7H3 (hB7H3)-Renca tumor were immunized with H1-pHMGB1/pB7H3, H1-pB7H3, H1-pHMGB1, or Mock vaccine. Compared to other control groups, the growth of the tumor was significantly inhibited in H1-pHMGB1/pB7H3 vaccine group. The increased proportion and mature of CD11c+ DCs were observed in the spleen of H1-pHMGB1/pB7H3 treated mice. Likewise, HMGB1 promoted B7H3 vaccine to induce tumor-specific CD8+ T cell proliferation and CTL responses. Beyond that, H1-pHMGB1/pB7H3 vaccine strengthened the induction of functional CD8+ T cells. With the depletion of CD8+ T cells, the anti-tumor effect of H1-pHMGB1/pB7H3 also disappeared, indicating that CD8+ T cells are the key factor of the anti-tumor activity of the vaccine. So, to sum up, H1-pHMGB1/pB7H3 vaccine could achieve the desired anti-tumor effect by enhancing the response of tumor-specific functional CD8+ T cell responses. H1 nanoparticle-based vaccines may have great potential and prospect in the treatment of primary solid tumors.
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Affiliation(s)
- Huanyou Sun
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Juan Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Wenwen Hu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Yinan Yan
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Zengli Guo
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Zichun Zhang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Yuxin Chen
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Xuefan Yao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Ling Teng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Xinyuan Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Liantao Li
- Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China
| | - Dafei Chai
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
| | - Junnian Zheng
- Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
| | - Gang Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, PR China.
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Kovaleva OV, Belova TP, Korotkova EA, Kushlinskii DN, Gratchev AN, Petrikova NA, Kudlay DA, Kushlinskii NE. Soluble B7-H3 in Ovarian Cancer and Its Predictive Value. Bull Exp Biol Med 2021; 171:472-474. [PMID: 34542756 DOI: 10.1007/s10517-021-05253-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Indexed: 11/29/2022]
Abstract
The content of the soluble form of protein of the key point of immunity B7-H3 (sB7-H3) in the blood plasma of 75 patients with epithelial ovarian cancer before treatment was measured by ELISA. It is known that B7-H3 belongs to the immunoglobulin superfamily (B7 molecule family) and is involved in the regulation of the immune response mediated by T cells. The sB7-H3 concentration correlated with the clinical and morphological parameters of ovarian cancer. The content of sB7-H3 was higher at the later stages of the disease, in the presence of ascites, and in patients with poorly differentiated ovarian cancer. It was revealed that increased plasma content of sB7-H3 in patients with epithelial ovarian cancer is associated with unfavorable prognosis of the disease. Therefore, sB7-H3 can be used as a prognostic marker in ovarian cancer patients.
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Affiliation(s)
- O V Kovaleva
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - T P Belova
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - E A Korotkova
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - D N Kushlinskii
- A. F. Tsyb Medical Radiological Research Center - Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - A N Gratchev
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N A Petrikova
- Ryazan Regional Clinical Oncological Center, Ryazan, Russia
| | - D A Kudlay
- Scientific Center Institute of Immunology, Federal Medical-Biological Agency of Russia, Moscow, Russia
| | - N E Kushlinskii
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
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Zhu J, Tang B, Gao Y, Xu S, Tu J, Wang Y, Yang W, Fang S, Weng Q, Zhao Z, Xu M, Yang Y, Chen M, Lu C, Ji J. Predictive Models for HCC Prognosis, Recurrence Risk, and Immune Infiltration Based on Two Exosomal Genes: MYL6B and THOC2. J Inflamm Res 2021; 14:4089-4109. [PMID: 34466015 PMCID: PMC8403029 DOI: 10.2147/jir.s315957] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 08/06/2021] [Indexed: 12/24/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is a heterogeneous molecular disease with complex molecular pathogenesis that influences the efficacy of therapies. Exosomes play a crucial role in tumorigenesis and poor disease outcomes in HCC. Objective The aim of this study was to identify the optimal gene set derived from exosomes in HCC with substantial predictive value to construct models for determining prognosis, recurrence risk and diagnosis and to identify candidates suitable for immunotherapy and chemotherapy, thereby providing new ideas for the individualized treatment of patients and for improving prognosis. Methods Weighted correlation network analysis (WGCNA) and univariate and multivariate Cox PH regression analyses were applied to identify exosome-related signatures in the TCGA and exoRbase databases associated with clinical relevance, immunogenic features and tumor progression in HCC. Cell experiments were performed to further confirm the oncogenic effect of MYL6B and THOC2. Results The models for prognosis and recurrence risk prediction were built based on two exosomal genes (MYL6B and THOC2) and were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC datasets, namely, the TCGA cohort (HR=2.5, P<0.001), the ICGC cohort (HR=3.15, P<0.001) and the GSE14520 cohort (HR=1.85, P=0.004). A higher recurrence probability was found in HCC patients with high recurrence risk than in HCC patients with low recurrence risk in the TCGA cohort (HR=2.44, P<0.001) and the GSE14520 cohort (HR=1.54, P=0.025). High prognostic risk patients had higher expression of immune checkpoint genes, such as PD1, B7H3, B7H5, CTLA4 and TIM3 (P<0.05). Diagnostic models based on the same two genes were able to accurately distinguish HCC patients from normal individuals and HCC from dysplastic nodules. Conclusion Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.
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Affiliation(s)
- Jinyu Zhu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
| | - Bufu Tang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People's Republic of China
| | - Yang Gao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Suqin Xu
- Clinical Laboratory, Fuyuan Hospital of Yiwu, Jinhua, 321000, People's Republic of China
| | - Jianfei Tu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Yajie Wang
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Weibin Yang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Shiji Fang
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Qiaoyou Weng
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Zhongwei Zhao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Min Xu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Yang Yang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Minjiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Chenying Lu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
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50
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Bi-specific and Tri-specific NK Cell Engagers: The New Avenue of Targeted NK Cell Immunotherapy. Mol Diagn Ther 2021; 25:577-592. [PMID: 34327614 DOI: 10.1007/s40291-021-00550-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2021] [Indexed: 02/01/2023]
Abstract
Natural killer (NK) cell-mediated cancer immunotherapy has grown significantly over the past two decades. More recently, multi-specific engagers have been developed as cancer therapeutics to effectively arm endogenous NK cells to more potently induce specific cytolytic responses against tumor targets. This review explores the bi- and tri-specific NK/tumor engagers that are emerging as a new generation of immunotherapeutics. These molecules vary in configuration, but they typically have small molecular weights and domains that engage specific tumor antigens and NK cell-activating receptors such as CD16, NKp30, NKp46, and NKG2D. They have demonstrated compelling potential in boosting NK cell cytotoxicity against specific tumor targets. This highly adaptable off-the-shelf platform, which in some formats also integrates cytokines, is poised to revolutionize targeted NK cell immunotherapy, either as a monotherapy or in combination with other effective anti-cancer therapies.
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