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Yang C, Wang P, Yang M, Lu Q, Zhu Z, Lu H, Li H, Zhang Z, Li M, Zhao L, Li J, Ling B, Fu X, Tong A. A fc-engineered NKG2D × B7-H3 bispecific antibody enhances the antitumor activity by orchestrating cytotoxic lymphocytes. Int Immunopharmacol 2025; 161:115032. [PMID: 40516256 DOI: 10.1016/j.intimp.2025.115032] [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: 01/01/2025] [Revised: 05/31/2025] [Accepted: 06/03/2025] [Indexed: 06/16/2025]
Abstract
B7-H3, an immune-checkpoint molecule that is overexpressed in several cancer types, has been identified as a promising immunotherapy target. However, most immunotherapy approaches against B7-H3+ tumor cells focus on manipulating the T cells. Natural killer (NK) cells, another important part of the cellular immune system, also exhibit anti-tumor properties and play complementary roles in tumor eradication with T cells. In this study, natural killer group 2D (NKG2D), an activating receptor in most cytotoxic immune cells, was selected for engaging NK cells. We obtained specific anti-NKG2D nanobodies via phage display and developed a series of B7-H3 × NKG2D bispecific antibodies (bsAb) with different formats to fight against the B7-H3+ tumor cells. Through functional comparison of candidate antibodies in vitro, B1-C53 was selected and further modified with the optimized Fc fragment (known as FC-C53) to enhance anti-tumor immunity by antibody-dependent cell-mediated cytotoxicity (ADCC). Stronger tumor lysis mediated by FC-C53 was demonstrated both in vitro and in vivo when simultaneously directed at both NK cells and CD8+ T cells, particularly after the additional administration of a B7-H3 × CD3 bispecific T cell engager that targets B7-H3 with another epitope. Overall, we provided a strategy based on the B7-H3 × NKG2D antibody to improve the anti-B7-H3 immunotherapy approaches by orchestrating cytotoxic lymphocytes.
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Affiliation(s)
- Chen Yang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ping Wang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingjun Yang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qizhong Lu
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhixiong Zhu
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Huaqing Lu
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hexian Li
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zongliang Zhang
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Meng Li
- Blood Research Laboratory, Chengdu Blood Center, Gongtong Street, Jinjiang District, Chengdu 610041, China
| | - Lizhou Zhao
- Blood Research Laboratory, Chengdu Blood Center, Gongtong Street, Jinjiang District, Chengdu 610041, China
| | - Jia Li
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Bo Ling
- Department of obstetrics and gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.
| | - Xuemei Fu
- Blood Research Laboratory, Chengdu Blood Center, Gongtong Street, Jinjiang District, Chengdu 610041, China.
| | - Aiping Tong
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
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Li M, Cao J, Wang Y, Zhao Z, Ai L, Zhang K. Predictive power of tertiary lymphoid structure for prognosis and neoadjuvant chemotherapy response in HER2-positive breast cancer. Medicine (Baltimore) 2025; 104:e42566. [PMID: 40489875 DOI: 10.1097/md.0000000000042566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/11/2025] Open
Abstract
This study evaluated the prognostic significance of tertiary lymphoid structures (TLS) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), focusing on their associations with survival outcomes, response to neoadjuvant therapy, and potential as a biomarker for personalized treatment strategies. Data from patients with HER2-positive BC in the METABRIC and The Cancer Genome Atlas databases were analyzed. TLS expression scores were calculated using gene set variation analysis, and their associations with survival outcomes were assessed. Immune cell infiltration, immune checkpoint expression, tumor mutational burden, and pathway enrichment were also evaluated. Data from the I-SPY2 clinical trial and a clinicopathological cohort of 19 patients from Xiangya Hospital were used to assess the relationship between TLS expression and pathological complete response following neoadjuvant therapy. High TLS expression was associated with improved survival and increased infiltration of antitumor immune cells. TLS-high tumors were enriched in immune-related pathways, whereas TLS-low tumors showed activation of proliferation and metabolism pathways. Patients with high TLS expression had better responses to neoadjuvant therapy, while those with low TLS expression derived greater benefit from dual-targeted treatments. TLS represents a promising biomarker for predicting survival and response to neoadjuvant therapy in HER2-positive BC, with potential to support personalized treatment strategies.
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Affiliation(s)
- Mengxi Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan, China
| | - Jing Cao
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan, China
| | - Yueheng Wang
- Department of Clinical Medicine, Queen Marry School, Nanchang University, Nanchang, Jiangxi, China
| | - Ziru Zhao
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan, China
| | - Liqiang Ai
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Kejing Zhang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan, China
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Nedeljković M, Vuletić A, Mirjačić Martinović K. Divide and Conquer-Targeted Therapy for Triple-Negative Breast Cancer. Int J Mol Sci 2025; 26:1396. [PMID: 40003864 PMCID: PMC11855393 DOI: 10.3390/ijms26041396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/31/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive and malignant type of breast cancer with limited treatment options and poor prognosis. One of the most significant impediments in TNBC treatment is the high heterogeneity of this disease, as highlighted by the detection of several molecular subtypes of TNBC. Each subtype is driven by distinct mutations and pathway aberrations, giving rise to specific molecular characteristics closely connected to clinical behavior, outcomes, and drug sensitivity. This review summarizes the knowledge regarding TNBC molecular subtypes and how it can be harnessed to devise tailored treatment strategies instead of blindly using targeted drugs. We provide an overview of novel targeted agents and key insights about new treatment modalities with an emphasis on the androgen receptor signaling pathway, cancer stem cell-associated pathways, phosphatidylinositol 3-kinase (PI3K)/AKT pathway, growth factor signaling, and immunotherapy.
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Affiliation(s)
- Milica Nedeljković
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.V.); (K.M.M.)
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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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Montoyo-Pujol YG, Ponce JJ, Delgado-García S, Martín TA, Ballester H, Castellón-Molla E, Ramos-Montoya A, Lozano-Cubo I, Sempere-Ortells JM, Peiró G. High CTLA-4 gene expression is an independent good prognosis factor in breast cancer patients, especially in the HER2-enriched subtype. Cancer Cell Int 2024; 24:371. [PMID: 39523362 PMCID: PMC11552348 DOI: 10.1186/s12935-024-03554-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-related death worldwide. This heterogeneous disease has been historically considered a non-immunogenic type of cancer. However, recent advances in immunotherapy have increased the interest in knowing the role of the immune checkpoints (IC) and other immune regulation pathways in this neoplasia. METHODS In this retrospective study, we evaluated the correlation of mRNA expression of CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3), JAK2, and FOXO1 with clinicopathological factors and BC patient's outcome by real-time quantitative polymerase chain reaction (qPCR). RESULTS Our results showed that immunoregulatory gene expression depends on BC immunophenotype being CTLA-4 and PDCD1 (PD1) overexpressed on triple-negative/basal-like (TN/BL) and luminal B/HER2-positive phenotypes, respectively, and CD276 (B7-H3), JAK2 and FOXO1 associated with both luminal A and luminal B/HER2-negative tumors. In addition, we found that these genes can also be related to aggressive and non-aggressive clinicopathological characteristics in BC. Finally, survival analysis showed that CTLA-4 expression levels emerge as a significant independent factor of good prognosis in BC patients, especially in the HER2-enriched subtype. CONCLUSION Considering all these data, we can conclude that the expression of immunoregulatory genes depends on tumor phenotype and has potential clinical implications in BC patients.
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Affiliation(s)
- Yoel G Montoyo-Pujol
- Research Unit, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain.
- Medical Oncology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain.
| | - José J Ponce
- Medical Oncology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Silvia Delgado-García
- Gynecology and Obstetrics Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Tina A Martín
- Gynecology and Obstetrics Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Hortensia Ballester
- Gynecology and Obstetrics Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Elena Castellón-Molla
- Pathology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Angela Ramos-Montoya
- Gynecology and Obstetrics Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Inmaculada Lozano-Cubo
- Medical Oncology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - J Miguel Sempere-Ortells
- Research Unit, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n. 03080-San Vicente del Raspeig, Alicante, 03010, Spain
| | - Gloria Peiró
- Research Unit, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain.
- Pathology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain.
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n. 03080-San Vicente del Raspeig, Alicante, 03010, Spain.
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6
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Hagelstein I, Wessling L, Rochwarger A, Zekri L, Klimovich B, Tegeler CM, Jung G, Schürch CM, Salih HR, Lutz MS. Targeting CD276 for T cell-based immunotherapy of breast cancer. J Transl Med 2024; 22:902. [PMID: 39367484 PMCID: PMC11452943 DOI: 10.1186/s12967-024-05689-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 09/17/2024] [Indexed: 10/06/2024] Open
Abstract
BACKGROUND Breast cancer (BC) is the most common malignancy in women. Immunotherapy has revolutionized treatment options in many malignancies, and the introduction of immune checkpoint inhibition yielded beneficial results also in BC. However, many BC patients are ineligible for this T cell-based therapy, others do not respond or only briefly. Thus, there remains a high medical need for new therapies, particularly for triple-negative BC. CD276 (B7-H3) is overexpressed in several tumors on both tumor cells and tumor vessels, constituting a promising target for immunotherapy. METHODS We analyzed tumor samples of 25 patients using immunohistochemistry to assess CD276 levels. The potential of CC-3, a novel bispecific CD276xCD3 antibody, for BC treatment was evaluated using various functional in vitro assays. RESULTS Pronounced expression of CD276 was observed in all analyzed tumor samples including triple negative BC. In analyses with BC cells, CC-3 induced profound T cell activation, proliferation, and T cell memory subset formation. Moreover, treatment with CC-3 induced cytokine secretion and potent tumor cell lysis. CONCLUSION Our findings characterize CD276 as promising target and preclinically document the therapeutic potential of CC-3 for BC treatment, providing a strong rationale for evaluation of CC-3 in BC patients in a clinical trial for which the recruitment has recently started.
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Affiliation(s)
- Ilona Hagelstein
- Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, German Cancer Consortium (DKTK), University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | - Laura Wessling
- Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, German Cancer Consortium (DKTK), University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
| | - Alexander Rochwarger
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Latifa Zekri
- Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, German Cancer Consortium (DKTK), University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
- Department for Immunology and German Cancer Consortium (DKTK), Eberhard Karls University, Tübingen, Germany
| | - Boris Klimovich
- Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, German Cancer Consortium (DKTK), University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | - Christian M Tegeler
- Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, German Cancer Consortium (DKTK), University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
- Department of Obstetrics and Gynecology, University Hospital Tübingen, Tübingen, Germany
- Department of Peptide-Based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, Tübingen, Germany
| | - Gundram Jung
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
- Department for Immunology and German Cancer Consortium (DKTK), Eberhard Karls University, Tübingen, Germany
| | - Christian M Schürch
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Helmut R Salih
- Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, German Cancer Consortium (DKTK), University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
| | - Martina S Lutz
- Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, German Cancer Consortium (DKTK), University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
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Yin N, Li X, Zhang X, Xue S, Cao Y, Niedermann G, Lu Y, Xue J. Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities. Signal Transduct Target Ther 2024; 9:126. [PMID: 38773064 PMCID: PMC11109181 DOI: 10.1038/s41392-024-01826-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 03/25/2024] [Accepted: 03/28/2024] [Indexed: 05/23/2024] Open
Abstract
Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.
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Affiliation(s)
- Nanhao Yin
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center & State Key Laboratory of Biotherapy, and The National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, 610041, Sichuan, PR China
| | - Xintong Li
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center & State Key Laboratory of Biotherapy, and The National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, 610041, Sichuan, PR China
| | - Xuanwei Zhang
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center & State Key Laboratory of Biotherapy, and The National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, 610041, Sichuan, PR China
| | - Shaolong Xue
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, Sichuan, PR China
| | - Yu Cao
- Department of Emergency Medicine, Laboratory of Emergency Medicine, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, 610041, Sichuan, PR China
- Institute of Disaster Medicine & Institute of Emergency Medicine, Sichuan University, No. 17, Gaopeng Avenue, Chengdu, 610041, Sichuan, PR China
| | - Gabriele Niedermann
- Department of Radiation Oncology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK) Partner Site DKTK-Freiburg, Robert-Koch-Strasse 3, 79106, Freiburg, Germany.
| | - You Lu
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center & State Key Laboratory of Biotherapy, and The National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, 610041, Sichuan, PR China.
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, No. 2222, Xinchuan Road, Chengdu, 610041, Sichuan, PR China.
| | - Jianxin Xue
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center & State Key Laboratory of Biotherapy, and The National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, 610041, Sichuan, PR China.
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, No. 2222, Xinchuan Road, Chengdu, 610041, Sichuan, PR China.
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8
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Sakunrangsit N, Khuisangeam N, Inthanachai T, Yodsurang V, Taechawattananant P, Suppipat K, Tawinwung S. Incorporating IL7 receptor alpha signaling in the endodomain of B7H3-targeting chimeric antigen receptor T cells mediates antitumor activity in glioblastoma. Cancer Immunol Immunother 2024; 73:98. [PMID: 38619641 PMCID: PMC11018726 DOI: 10.1007/s00262-024-03685-7] [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: 09/29/2023] [Accepted: 03/19/2024] [Indexed: 04/16/2024]
Abstract
CAR-T-cell therapy has shown promise in treating hematological malignancies but faces challenges in treating solid tumors due to impaired T-cell function in the tumor microenvironment. To provide optimal T-cell activation, we developed a B7 homolog 3 protein (B7H3)-targeting CAR construct consisting of three activation signals: CD3ζ (signal 1), 41BB (signal 2), and the interleukin 7 receptor alpha (IL7Rα) cytoplasmic domain (signal 3). We generated B7H3 CAR-T cells with different lengths of the IL7Rα cytoplasmic domain, including the full length (IL7R-L), intermediate length (IL7R-M), and short length (IL7R-S) domains, and evaluated their functionality in vitro and in vivo. All the B7H3-IL7Rα CAR-T cells exhibited a less differentiated phenotype and effectively eliminated B7H3-positive glioblastoma in vitro. Superiority was found in B7H3 CAR-T cells contained the short length of the IL7Rα cytoplasmic domain. Integration of the IL7R-S cytoplasmic domain maintained pSTAT5 activation and increased T-cell proliferation while reducing activation-induced cell death. Moreover, RNA-sequencing analysis of B7H3-IL7R-S CAR-T cells after coculture with a glioblastoma cell line revealed downregulation of proapoptotic genes and upregulation of genes associated with T-cell proliferation compared with those in 2nd generation B7H3 CAR-T cells. In animal models, compared with conventional CAR-T cells, B7H3-IL7R-S CAR-T cells suppressed tumor growth and prolonged overall survival. Our study demonstrated the therapeutic potential of IL7Rα-incorporating CAR-T cells for glioblastoma treatment, suggesting a promising strategy for augmenting the effectiveness of CAR-T cell therapy.
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Affiliation(s)
- Nithidol Sakunrangsit
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Nattarika Khuisangeam
- Medical Microbiology, Interdisciplinary and International Program, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Thananya Inthanachai
- Medical Microbiology, Interdisciplinary and International Program, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Varalee Yodsurang
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Pasrawin Taechawattananant
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Koramit Suppipat
- Department of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Cellular Immunotherapy Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand
- Thailand Hub of Talents in Cancer Immunotherapy (TTCI), Bangkok, 10330, Thailand
| | - Supannikar Tawinwung
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
- Cellular Immunotherapy Research Unit, Chulalongkorn University, Bangkok, 10330, Thailand.
- Thailand Hub of Talents in Cancer Immunotherapy (TTCI), Bangkok, 10330, Thailand.
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9
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Joshi V, Beecher K, Lim M, Stacey A, Feng Y, Jat PS, Duijf PHG, Simpson PT, Lakhani SR, McCart Reed AE. B7-H3 Expression in Breast Cancer and Brain Metastasis. Int J Mol Sci 2024; 25:3976. [PMID: 38612786 PMCID: PMC11012592 DOI: 10.3390/ijms25073976] [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: 02/27/2024] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Brain metastasis is a significant challenge for some breast cancer patients, marked by its aggressive nature, limited treatment options, and poor clinical outcomes. Immunotherapies have emerged as a promising avenue for brain metastasis treatment. B7-H3 (CD276) is an immune checkpoint molecule involved in T cell suppression, which is associated with poor survival in cancer patients. Given the increasing number of clinical trials using B7-H3 targeting CAR T cell therapies, we examined B7-H3 expression across breast cancer subtypes and in breast cancer brain metastases to assess its potential as an interventional target. B7-H3 expression was investigated using immunohistochemistry on tissue microarrays of three clinical cohorts: (i) unselected primary breast cancers (n = 347); (ii) brain metastatic breast cancers (n = 61) and breast cancer brain metastases (n = 80, including a subset of 53 patient-matched breast and brain metastasis cases); and (iii) mixed brain metastases from a range of primary tumours (n = 137). In primary breast cancers, B7-H3 expression significantly correlated with higher tumour grades and aggressive breast cancer subtypes, as well as poorer 5-year survival outcomes. Subcellular localisation of B7-H3 impacted breast cancer-specific survival, with cytoplasmic staining also correlating with a poorer outcome. Its expression was frequently detected in brain metastases from breast cancers, with up to 90% expressing B7-H3. However, not all brain metastases showed high levels of expression, with those from colorectal and renal tumours showing a low frequency of B7-H3 expression (0/14 and 2/16, respectively). The prevalence of B7-H3 expression in breast cancers and breast cancer brain metastases indicates potential opportunities for B7-H3 targeted therapies in breast cancer management.
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Affiliation(s)
- Vaibhavi Joshi
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia; (V.J.); (K.B.); (M.L.); (A.S.); (Y.F.); (P.T.S.)
| | - Kate Beecher
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia; (V.J.); (K.B.); (M.L.); (A.S.); (Y.F.); (P.T.S.)
| | - Malcolm Lim
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia; (V.J.); (K.B.); (M.L.); (A.S.); (Y.F.); (P.T.S.)
| | - Andrew Stacey
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia; (V.J.); (K.B.); (M.L.); (A.S.); (Y.F.); (P.T.S.)
| | - Yufan Feng
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia; (V.J.); (K.B.); (M.L.); (A.S.); (Y.F.); (P.T.S.)
| | - Parmjit S. Jat
- MRC Prion Unit at UCL, Institute of Prion Diseases, Courtauld Building, London W1W 7FF, UK;
| | - Pascal H. G. Duijf
- Centre for Cancer Biology, Clinical and Health Sciences, University of South Australia & SA Pathology, Adelaide 5001, Australia;
| | - Peter T. Simpson
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia; (V.J.); (K.B.); (M.L.); (A.S.); (Y.F.); (P.T.S.)
| | - Sunil R. Lakhani
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia; (V.J.); (K.B.); (M.L.); (A.S.); (Y.F.); (P.T.S.)
- Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane 4029, Australia
| | - Amy E. McCart Reed
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia; (V.J.); (K.B.); (M.L.); (A.S.); (Y.F.); (P.T.S.)
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10
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Xu YH, Lu P, Gao MC, Wang R, Li YY, Guo RQ, Zhang WS, Song JX. Nomogram based on multimodal magnetic resonance combined with B7-H3mRNA for preoperative lymph node prediction in esophagus cancer. World J Clin Oncol 2024; 15:419-433. [PMID: 38576593 PMCID: PMC10989267 DOI: 10.5306/wjco.v15.i3.419] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/15/2024] [Accepted: 02/06/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND Accurate preoperative prediction of lymph node metastasis (LNM) in esophageal cancer (EC) patients is of crucial clinical significance for treatment planning and prognosis. AIM To develop a clinical radiomics nomogram that can predict the preoperative lymph node (LN) status in EC patients. METHODS A total of 32 EC patients confirmed by clinical pathology (who underwent surgical treatment) were included. Real-time fluorescent quantitative reverse transcription-polymerase chain reaction was used to detect the expression of B7-H3 mRNA in EC tissue obtained during preoperative gastroscopy, and its correlation with LNM was analyzed. Radiomics features were extracted from multi-modal magnetic resonance imaging of EC using Pyradiomics in Python. Feature extraction, data dimensionality reduction, and feature selection were performed using XGBoost model and leave-one-out cross-validation. Multivariable logistic regression analysis was used to establish the prediction model, which included radiomics features, LN status from computed tomography (CT) reports, and B7-H3 mRNA expression, represented by a radiomics nomogram. Receiver operating characteristic area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the predictive performance and clinical application value of the model. RESULTS The relative expression of B7-H3 mRNA in EC patients with LNM was higher than in those without metastasis, and the difference was statistically significant (P < 0.05). The AUC value in the receiver operating characteristic (ROC) curve was 0.718 (95%CI: 0.528-0.907), with a sensitivity of 0.733 and specificity of 0.706, indicating good diagnostic performance. The individualized clinical prediction nomogram included radiomics features, LN status from CT reports, and B7-H3 mRNA expression. The ROC curve demonstrated good diagnostic value, with an AUC value of 0.765 (95%CI: 0.598-0.931), sensitivity of 0.800, and specificity of 0.706. DCA indicated the practical value of the radiomics nomogram in clinical practice. CONCLUSION This study developed a radiomics nomogram that includes radiomics features, LN status from CT reports, and B7-H3 mRNA expression, enabling convenient preoperative individualized prediction of LNM in EC patients.
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Affiliation(s)
- Yan-Han Xu
- School of Clinical Sciences, Graduate School of Nantong University, Yancheng 226019, Jiangsu Province, China
- Department of Thoracic Surgery, Yancheng Third People's Hospital, The Affiliated Hospital 6 of Nantong University, Yancheng 224000, Jiangsu Province, China
| | - Peng Lu
- Department of Imaging, Yancheng Third People's Hospital, The Affiliated Hospital 6 of Nantong University, Yancheng 224000, Jiangsu Province, China
| | - Ming-Cheng Gao
- School of Clinical Sciences, Graduate School of Nantong University, Yancheng 226019, Jiangsu Province, China
- Department of Thoracic Surgery, Yancheng Third People's Hospital, The Affiliated Hospital 6 of Nantong University, Yancheng 224000, Jiangsu Province, China
| | - Rui Wang
- School of Clinical Sciences, Graduate School of Nantong University, Yancheng 226019, Jiangsu Province, China
- Department of Thoracic Surgery, Yancheng Third People's Hospital, The Affiliated Hospital 6 of Nantong University, Yancheng 224000, Jiangsu Province, China
| | - Yang-Yang Li
- School of Clinical Sciences, Graduate School of Nantong University, Yancheng 226019, Jiangsu Province, China
- Department of Thoracic Surgery, Yancheng Third People's Hospital, The Affiliated Hospital 6 of Nantong University, Yancheng 224000, Jiangsu Province, China
| | - Rong-Qi Guo
- School of Clinical Sciences, Graduate School of Nantong University, Yancheng 226019, Jiangsu Province, China
- Department of Thoracic Surgery, Yancheng Third People's Hospital, The Affiliated Hospital 6 of Nantong University, Yancheng 224000, Jiangsu Province, China
| | - Wei-Song Zhang
- School of Clinical Sciences, Graduate School of Nantong University, Yancheng 226019, Jiangsu Province, China
- Department of Thoracic Surgery, Yancheng Third People's Hospital, The Affiliated Hospital 6 of Nantong University, Yancheng 224000, Jiangsu Province, China
| | - Jian-Xiang Song
- Department of Thoracic Surgery, Yancheng Third People's Hospital, The Affiliated Hospital 6 of Nantong University, Yancheng 224000, Jiangsu Province, China
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11
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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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12
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Sun Y, Liu Q, Zhong S, Wei R, Luo JL. Triple-Negative Breast Cancer Intrinsic FTSJ1 Favors Tumor Progression and Attenuates CD8+ T Cell Infiltration. Cancers (Basel) 2024; 16:597. [PMID: 38339348 PMCID: PMC10854779 DOI: 10.3390/cancers16030597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 01/21/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
FtsJ RNA 2'-O-methyltransferase 1 (FTSJ1) is a member of the methyltransferase superfamily and is involved in the processing and modification of ribosomal RNA. We herein demonstrate that FTSJ1 favors TNBC progression. The knockdown of FTSJ1 inhibits TNBC cell proliferation and development, induces apoptosis of cancer cells, and increases the sensitivity of TNBC cells to T-cell-mediated cytotoxicity. Furthermore, the high expression of FTSJ1 in TNBC attenuates CD8+T cell infiltration in the tumor microenvironment (TME) correlated with poorer prognosis for clinical TNBC patients. In this study, we establish that FTSJ1 acts as a tumor promotor, is involved in cancer immune evasion, and may serve as a potential immunotherapy target in TNBC.
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Affiliation(s)
- Yangqing Sun
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China; (Y.S.); (Q.L.)
| | - Qingqing Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China; (Y.S.); (Q.L.)
| | - Shangwei Zhong
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China;
| | - Rui Wei
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China; (Y.S.); (Q.L.)
| | - Jun-Li Luo
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China; (Y.S.); (Q.L.)
- The Cancer Research Institute and the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China;
- National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, China
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13
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Mei J, Cai Y, Zhu H, Jiang Y, Fu Z, Xu J, Chen L, Yang K, Zhao J, Song C, Zhang Y, Mao W, Yin Y. High B7-H3 expression with low PD-L1 expression identifies armored-cold tumors in triple-negative breast cancer. NPJ Breast Cancer 2024; 10:11. [PMID: 38280882 PMCID: PMC10821876 DOI: 10.1038/s41523-024-00618-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 01/06/2024] [Indexed: 01/29/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is generally regarded as the most aggressive subtype among breast cancers, but exhibits higher chemotherapeutic and immunotherapeutic responses due to its unique immunogenicity. Thus, appropriate discrimination of subtypes is critical for guiding therapeutic options in clinical practice. In this research, using multiple in-house and public cohorts, we investigated the expression features and immuno-correlations of B7-H3 in breast cancer and checked the anti-tumor effect of the B7-H3 monoclonal antibody in a mouse model. We also developed a novel classifier combining B7-H3 and PD-L1 expression in TNBC. B7-H3 was revealed to be related to immuno-cold features and accumulated collagen in TNBC. In addition, targeting B7-H3 using the monoclonal antibody significantly suppressed mouse TNBC growth, reversed the armored-cold phenotype, and also boosted anti-PD-1 immunotherapy. In addition, patients with B7-H3 high and PD-L1 low expression showed the lowest anti-tumor immune infiltration, the highest collagen level, and the lowest therapeutic responses to multiple therapies, which mostly belong to armored-cold tumors. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression, which leads to a novel approach for the management of TNBC.
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Affiliation(s)
- Jie Mei
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
- The First Clinical Medicine College, Nanjing Medical University, Wuxi, 214023, China
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yun Cai
- Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, China
| | - Hongjun Zhu
- Department of Oncology, Nantong Third People's Hospital Affiliated to Nantong University, Nantong, 226006, China
| | - Ying Jiang
- Department of Gynecology, The Obstetrics and Gynecology Hospital Affiliated to Jiangnan University, Wuxi, 214023, China
| | - Ziyi Fu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
| | - Junying Xu
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Lingyan Chen
- Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, China
| | - Kai Yang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China
- The First Clinical Medicine College, Nanjing Medical University, Wuxi, 214023, China
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Jinlu Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Chenghu Song
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yan Zhang
- Wuxi Maternal and Child Health Care Hospital, Wuxi Medical Center of Nanjing Medical University, Wuxi, 214023, China.
- Department of Gynecology, The Obstetrics and Gynecology Hospital Affiliated to Jiangnan University, Wuxi, 214023, China.
| | - Wenjun Mao
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China.
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, 211166, China.
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14
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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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15
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Koumprentziotis IA, Theocharopoulos C, Foteinou D, Angeli E, Anastasopoulou A, Gogas H, Ziogas DC. New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3. Vaccines (Basel) 2024; 12:54. [PMID: 38250867 PMCID: PMC10820813 DOI: 10.3390/vaccines12010054] [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: 11/13/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.
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16
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Önder CE, Moustafa-Oglou M, Schröder SM, Hartkopf AD, Koch A, Seitz CM. Precision Immunotherapy Utilizing Adapter CAR-T Cells (AdCAR-T) in Metastatic Breast Cancer Leads to Target Specific Lysis. Cancers (Basel) 2023; 16:168. [PMID: 38201595 PMCID: PMC10778501 DOI: 10.3390/cancers16010168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/22/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
A frequent symptom of metastasized breast cancer (BC) includes the development of malignant pleural effusion (MPE), which contains malignant cells derived from the primary tumor site. The poor prognosis of MPE in metastasized BC indicates the necessity for dependable precision oncology and the importance of models representing the heterogenous nature of metastatic BC. In this study, we cultured MPE-derived metastatic tumor cells from four advanced BC patients using organoid technology. We assessed the expression of tumor-associated antigens on MPE-derived organoid lines by flow cytometry (FC). Based on an individual antigen expression pattern, patient-derived organoids were treated with adapter CAR-T cells (AdCAR-T) and biotinylated monoclonal antibodies targeting CD276, HER2, EGFR, TROP2, or EpCAM. Co-culture assays revealed specific organoid lysis by AdCAR-T depending on individual antigen expression patterns. Our results demonstrate that MPE-derived organoids can serve as a reliable tool for assessing the efficacy of AdCAR-T on metastatic BC in a patient-individualized manner. This approach could potentially be applied in a preclinical setting to instruct therapy decisions. Further, our study demonstrates the feasibility of precision immunotherapy utilizing AdCAR-T to target patient-individualized antigen patterns.
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Affiliation(s)
- Cansu E. Önder
- Research Institute for Women’s Health, University of Tübingen, 72076 Tübingen, Germany;
| | - Moustafa Moustafa-Oglou
- Department of Pediatric Oncology and Hematology, University Hospital Tübingen, 72076 Tübingen, Germany;
| | - Sarah M. Schröder
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, 89081 Ulm, Germany
- Department of Peptide-Based Immunotherapy, University and University Hospital Tübingen, 72076 Tübingen, Germany
| | - Andreas D. Hartkopf
- Department of Women’s Health, University of Tübingen, 72076 Tübingen, Germany
| | - André Koch
- Research Institute for Women’s Health, University of Tübingen, 72076 Tübingen, Germany;
- Department of Women’s Health, University of Tübingen, 72076 Tübingen, Germany
| | - Christian M. Seitz
- Department of Pediatric Oncology and Hematology, University Hospital Tübingen, 72076 Tübingen, Germany;
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, 72076 Tübingen, Germany
- German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership between German Cancer Research Center (DKFZ) and University Hospital Tübingen, 81675 Munich, Germany
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Belluomini L, Sposito M, Avancini A, Insolda J, Milella M, Rossi A, Pilotto S. Unlocking New Horizons in Small-Cell Lung Cancer Treatment: The Onset of Antibody-Drug Conjugates. Cancers (Basel) 2023; 15:5368. [PMID: 38001628 PMCID: PMC10670928 DOI: 10.3390/cancers15225368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/02/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
Small-cell lung cancer (SCLC) is a highly aggressive disease, accounting for about 15% of all lung cancer cases. Despite initial responses to chemoimmunotherapy, SCLC recurs and becomes resistant to treatment. Recently, antibody-drug conjugates (ADCs) have emerged as a promising therapeutic option for SCLC. ADCs consist of an antibody that specifically targets a tumor antigen linked to a cytotoxic drug. The antibody delivers the drug directly to the cancer cells, minimizing off-target toxicity and improving the therapeutic index. Several ADCs targeting different tumor antigens are currently being evaluated in clinical trials for SCLC. Despite the negative results of rovalpituzumab tesirine (Rova-T), other ADCs targeting different antigens, such as B7-H3, seizure-related homolog 6 (SEZ6), and CEACAM5, have also been investigated in clinical trials, including for SCLC, and their results suggest preliminary activity, either alone or in combination with other therapies. More recently, sacituzumab govitecan, an anti-TROP2 ADC, demonstrated promising activity in lung cancer, including SCLC. Furthermore, an anti-B7-H3 (CD276), ifinatamab deruxtecan (DS7300A), showed a high response rate and durable responses in heavily pretreated SCLC. Overall, ADCs represent an intriguing approach to treating SCLC, particularly in the relapsed or refractory setting. Further studies are needed to determine their efficacy and safety and the best location in the treatment algorithm for SCLC. In this review, we aim to collect and describe the results regarding the past, the present, and the future of ADCs in SCLC.
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Affiliation(s)
- Lorenzo Belluomini
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (L.B.); (M.S.); (A.A.); (J.I.); (M.M.); (S.P.)
| | - Marco Sposito
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (L.B.); (M.S.); (A.A.); (J.I.); (M.M.); (S.P.)
| | - Alice Avancini
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (L.B.); (M.S.); (A.A.); (J.I.); (M.M.); (S.P.)
| | - Jessica Insolda
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (L.B.); (M.S.); (A.A.); (J.I.); (M.M.); (S.P.)
| | - Michele Milella
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (L.B.); (M.S.); (A.A.); (J.I.); (M.M.); (S.P.)
| | - Antonio Rossi
- Therapeutic Science & Strategy Unit, Oncology Centre of Excellence, IQVIA, 20019 Milan, Italy
| | - Sara Pilotto
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (L.B.); (M.S.); (A.A.); (J.I.); (M.M.); (S.P.)
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18
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Ahmad A, Khan P, Rehman AU, Batra SK, Nasser MW. Immunotherapy: an emerging modality to checkmate brain metastasis. Mol Cancer 2023; 22:111. [PMID: 37454123 PMCID: PMC10349473 DOI: 10.1186/s12943-023-01818-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/06/2023] [Indexed: 07/18/2023] Open
Abstract
The diagnosis of brain metastasis (BrM) has historically been a dooming diagnosis that is nothing less than a death sentence, with few treatment options for palliation or prolonging life. Among the few treatment options available, brain radiotherapy (RT) and surgical resection have been the backbone of therapy. Within the past couple of years, immunotherapy (IT), alone and in combination with traditional treatments, has emerged as a reckoning force to combat the spread of BrM and shrink tumor burden. This review compiles recent reports describing the potential role of IT in the treatment of BrM in various cancers. It also examines the impact of the tumor microenvironment of BrM on regulating the spread of cancer and the role IT can play in mitigating that spread. Lastly, this review also focuses on the future of IT and new clinical trials pushing the boundaries of IT in BrM.
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Affiliation(s)
- Aatiya Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Asad Ur Rehman
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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19
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Hińcza-Nowak K, Kowalik A, Walczyk A, Pałyga I, Gąsior-Perczak D, Płusa A, Kopczyński J, Chrapek M, Góźdź S, Kowalska A. CD276 as a Candidate Target for Immunotherapy in Medullary Thyroid Cancer. Int J Mol Sci 2023; 24:10019. [PMID: 37373167 DOI: 10.3390/ijms241210019] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/06/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Medullary thyroid cancer (MTC) is a rare malignancy, and the treatment of metastatic MTC is challenging. In previous work, immune profiling (RNA-Seq) of MTC identified CD276 as a potential target for immunotherapy. CD276 expression was 3-fold higher in MTC cells than in normal tissues. Paraffin blocks from patients with MTC were analyzed by immunohistochemistry to confirm the results of RNA-Seq. Serial sections were incubated with anti-CD276 antibody, and scored according to staining intensity and the percentage of immunoreactive cells. The results showed that CD276 expression was higher in MTC tissues than in controls. A lower percentage of immunoreactive cells correlated with the absence of lateral node metastasis, lower levels of calcitonin after surgery, no additional treatments, and remission. There were statistically significant associations of intensity of immunostaining and percentage of CD276 immunoreactive cells with clinical factors and the course of the disease. These results suggest that targeting this immune checkpoint molecule CD276 could be a promising strategy for the treatment of MTC.
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Affiliation(s)
- Kinga Hińcza-Nowak
- Department of Molecular Diagnostics, Holycross Cancer Centre, 25-734 Kielce, Poland
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
| | - Artur Kowalik
- Department of Molecular Diagnostics, Holycross Cancer Centre, 25-734 Kielce, Poland
- Division of Medical Biology, Institute of Biology, Jan Kochanowski University, 25-406 Kielce, Poland
| | - Agnieszka Walczyk
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
- Collegium Medicum, Jan Kochanowski University, 25-319 Kielce, Poland
| | - Iwona Pałyga
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
- Collegium Medicum, Jan Kochanowski University, 25-319 Kielce, Poland
| | - Danuta Gąsior-Perczak
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
- Collegium Medicum, Jan Kochanowski University, 25-319 Kielce, Poland
| | - Agnieszka Płusa
- Surgical Pathology, Holycross Cancer Centre, 25-734 Kielce, Poland
| | | | - Magdalena Chrapek
- Faculty of Natural Sciences, Jan Kochanowski University, 25-406 Kielce, Poland
| | - Stanisław Góźdź
- Collegium Medicum, Jan Kochanowski University, 25-319 Kielce, Poland
- Clinical Oncology, Holycross Cancer Centre, 25-734 Kielce, Poland
| | - Aldona Kowalska
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
- Collegium Medicum, Jan Kochanowski University, 25-319 Kielce, Poland
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20
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Shi W, Wang Y, Zhao Y, Kim JJ, Li H, Meng C, Chen F, Zhang J, Mak DH, Van V, Leo J, Croix BS, Aparicio A, Zhao D. Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies. Sci Transl Med 2023; 15:eadf6724. [PMID: 37163614 PMCID: PMC10574140 DOI: 10.1126/scitranslmed.adf6724] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 04/17/2023] [Indexed: 05/12/2023]
Abstract
Checkpoint immunotherapy has yielded meaningful responses across many cancers but has shown modest efficacy in advanced prostate cancer. B7 homolog 3 protein (B7-H3/CD276) is an immune checkpoint molecule and has emerged as a promising therapeutic target. However, much remains to be understood regarding B7-H3's role in cancer progression, predictive biomarkers for B7-H3-targeted therapy, and combinatorial strategies. Our multi-omics analyses identified B7-H3 as one of the most abundant immune checkpoints in prostate tumors containing PTEN and TP53 genetic inactivation. Here, we sought in vivo genetic evidence for, and mechanistic understanding of, the role of B7-H3 in PTEN/TP53-deficient prostate cancer. We found that loss of PTEN and TP53 induced B7-H3 expression by activating transcriptional factor Sp1. Prostate-specific deletion of Cd276 resulted in delayed tumor progression and reversed the suppression of tumor-infiltrating T cells and NK cells in Pten/Trp53 genetically engineered mouse models. Furthermore, we tested the efficacy of the B7-H3 inhibitor in preclinical models of castration-resistant prostate cancer (CRPC). We demonstrated that enriched regulatory T cells and elevated programmed cell death ligand 1 (PD-L1) in myeloid cells hinder the therapeutic efficacy of B7-H3 inhibition in prostate tumors. Last, we showed that B7-H3 inhibition combined with blockade of PD-L1 or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) achieved durable antitumor effects and had curative potential in a PTEN/TP53-deficient CRPC model. Given that B7-H3-targeted therapies have been evaluated in early clinical trials, our studies provide insights into the potential of biomarker-driven combinatorial immunotherapy targeting B7-H3 in prostate cancer, among other malignancies.
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Affiliation(s)
- Wei Shi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yin Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yuehui Zhao
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Justin Jimin Kim
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Biology, Colby College, Waterville, ME 04901, USA
| | - Haoyan Li
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Chenling Meng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Feiyu Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jie Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Duncan H. Mak
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vivien Van
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Javier Leo
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Brad St. Croix
- Tumor Angiogenesis Unit, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
| | - Ana Aparicio
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Di Zhao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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21
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Getu AA, Tigabu A, Zhou M, Lu J, Fodstad Ø, Tan M. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Mol Cancer 2023; 22:43. [PMID: 36859240 PMCID: PMC9979440 DOI: 10.1186/s12943-023-01751-9] [Citation(s) in RCA: 95] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
B7-H3 (CD276), a member of the B7 family of proteins, is a key player in cancer progression. This immune checkpoint molecule is selectively expressed in both tumor cells and immune cells within the tumor microenvironment. In addition to its immune checkpoint function, B7-H3 has been linked to tumor cell proliferation, metastasis, and therapeutic resistance. Furthermore, its drastic difference in protein expression levels between normal and tumor tissues suggests that targeting B7-H3 with drugs would lead to cancer-specific toxicity, minimizing harm to healthy cells. These properties make B7-H3 a promising target for cancer therapy.Recently, important advances in B7-H3 research and drug development have been reported, and these new findings, including its involvement in cellular metabolic reprograming, cancer stem cell enrichment, senescence and obesity, have expanded our knowledge and understanding of this molecule, which is important in guiding future strategies for targeting B7-H3. In this review, we briefly discuss the biology and function of B7-H3 in cancer development. We emphasize more on the latest findings and their underlying mechanisms to reflect the new advances in B7-H3 research. In addition, we discuss the new improvements of B-H3 inhibitors in cancer drug development.
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Affiliation(s)
- Ayechew Adera Getu
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
- Department of Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Abiye Tigabu
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Ming Zhou
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jianrong Lu
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, USA
| | - Øystein Fodstad
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
| | - Ming Tan
- Institute of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
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22
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Montoyo-Pujol YG, García-Escolano M, Ponce JJ, Delgado-García S, Martín TA, Ballester H, Castellón-Molla E, Martínez-Peinado P, Pascual-García S, Sempere-Ortells JM, Peiró G. Variable Intrinsic Expression of Immunoregulatory Biomarkers in Breast Cancer Cell Lines, Mammospheres, and Co-Cultures. Int J Mol Sci 2023; 24:4478. [PMID: 36901916 PMCID: PMC10003642 DOI: 10.3390/ijms24054478] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 02/13/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Advances in immunotherapy have increased interest in knowing the role of the immune system in breast cancer (BC) pathogenesis. Therefore, immune checkpoints (IC) and other pathways related to immune regulation, such as JAK2 and FoXO1, have emerged as potential targets for BC treatment. However, their intrinsic gene expression in vitro has not been extensively studied in this neoplasia. Thus, we evaluated the mRNA expression of tumor-cell-intrinsic CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3), JAK2, and FoXO1 in different BC cell lines, derived mammospheres, and co-cultures with peripheral blood mononuclear cells (PBMCs) by real-time quantitative polymerase chain reaction (qRT-PCR). Our results showed that intrinsic CTLA-4, CD274 (PD-L1), and PDCD1LG2 (PD-L2) were highly expressed in triple-negative cell lines, while CD276 was predominantly overexpressed in luminal cell lines. In contrast, JAK2 and FoXO1 were under-expressed. Moreover, high levels of CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), and JAK2 were found after mammosphere formation. Finally, the interaction between BC cell lines and peripheral blood mononuclear cells (PBMCs) stimulates the intrinsic expression of CTLA-4, PCDC1 (PD1), CD274 (PD-L1), and PDCD1LG2 (PD-L2). In conclusion, the intrinsic expression of immunoregulatory genes seems very dynamic, depending on BC phenotype, culture conditions, and tumor-immune cell interactions.
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Affiliation(s)
- Yoel Genaro Montoyo-Pujol
- Research Unit, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
- Medical Oncology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Marta García-Escolano
- Research Unit, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - José J. Ponce
- Medical Oncology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Silvia Delgado-García
- Gynecology and Obstetrics Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Tina Aurora Martín
- Gynecology and Obstetrics Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Hortensia Ballester
- Gynecology and Obstetrics Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Elena Castellón-Molla
- Pathology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Pascual Martínez-Peinado
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
| | - Sandra Pascual-García
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
| | - José Miguel Sempere-Ortells
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Gloria Peiró
- Research Unit, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
- Pathology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
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23
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Zhang Q, Zhang Z, Liu G, Li D, Gu Z, Zhang L, Pan Y, Cui X, Wang L, Liu G, Tian X, Zhang Z. B7-H3 targeted CAR-T cells show highly efficient anti-tumor function against osteosarcoma both in vitro and in vivo. BMC Cancer 2022; 22:1124. [PMID: 36320072 PMCID: PMC9628043 DOI: 10.1186/s12885-022-10229-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 10/25/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Osteosarcoma (OS) mainly happens in children and youths. Surgery, radiotherapy and chemotherapy are the common therapies for osteosarcoma treatment but all their anti-tumor effects are limited. In recent years, a new cellular therapy, CAR-T, a cellular immunotherapy with genetically engineered T cells bearing chimeric antigen receptor targeting specific tumor-associated antigen, has been proved to be an effective therapy against acute lymphoblastic leukemia. Thus, CAR-T is a potentially effective therapy for osteosarcoma treatment. METHODS A CAR gene targeting B7-H3 antigen was constructed into lentiviral vector through molecular biology techniques. Then, the CAR gene was transferred to T cells through lentiviral delivery system, and the CAR-T cells were largely expanded using in vitro culture technology. The in vitro anti-tumor effect of CAR-T cells was evaluated through Real Time Cell Analysis system (RTCA) and ELISA assay. The in vivo anti-tumor capabilities of CAR-T cells were evaluated using the patient-derived xenografts (PDX) model of osteosarcoma. RESULTS The third-generation CAR-T cells we constructed could target the B7-H3 antigen, and the phenotype of CAR-T cells was consistent with normal T cells; The CAR-T cells showed superior antitumor effects both in vitro and in vivo. CONCLUSION Our study showed that B7-H3 targeted CAR-T cells had high anti-tumor efficacy against osteosarcoma both in vitro and in vivo, which proved that B7-H3 targeted CAR-T therapy is potentially effective for osteosarcoma treatment.
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Affiliation(s)
- Qian Zhang
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231 China
| | - Zhiqiang Zhang
- grid.411333.70000 0004 0407 2968Department of Pediatric Orthopedics, National Children’s Medical Center & Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Guodi Liu
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231 China ,grid.28056.390000 0001 2163 4895State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237 China
| | - Dehua Li
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231 China
| | - Zhangjie Gu
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231 China
| | - Linsong Zhang
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231 China
| | - Yingjiao Pan
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231 China
| | - Xingbing Cui
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231 China
| | - Lu Wang
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231 China
| | - Guoping Liu
- grid.411525.60000 0004 0369 1599Department of General Surgery, Changhai Hospital, Shanghai, 200433 China
| | - Xiaoli Tian
- Shanghai Yihao Biological Technology Co., Ltd, Shanghai, 200231 China ,Shanghai Beautiful Life Medical Technology Co., Ltd., Shanghai, 200231 China
| | - Ziming Zhang
- grid.412987.10000 0004 0630 1330Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092 China ,grid.415625.10000 0004 0467 3069Department of Orthopaedics, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062 China
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24
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Zhao B, Li H, Xia Y, Wang Y, Wang Y, Shi Y, Xing H, Qu T, Wang Y, Ma W. Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy. J Hematol Oncol 2022; 15:153. [PMID: 36284349 PMCID: PMC9597993 DOI: 10.1186/s13045-022-01364-7] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/30/2022] [Indexed: 11/28/2022] Open
Abstract
Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.
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Affiliation(s)
- Binghao Zhao
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Huanzhang Li
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yu Xia
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yaning Wang
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yuekun Wang
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yixin Shi
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Hao Xing
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Tian Qu
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yu Wang
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
| | - Wenbin Ma
- grid.506261.60000 0001 0706 7839Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 People’s Republic of China ,grid.506261.60000 0001 0706 7839State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China
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Axilla lymph node dissection can be safely omitted in patients with 1-2 positive sentinel nodes receiving mastectomy: a large multi-institutional study and a systemic meta-analysis. Breast Cancer Res Treat 2022; 196:129-141. [PMID: 36076127 DOI: 10.1007/s10549-022-06727-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 08/26/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE This study aimed to evaluate whether axillary lymph node dissection (ALND) can be omitted in patients with 1-2 positive sentinel lymph nodes (SLNs) who received total mastectomy (TM). METHODS Consecutive breast cancer patients with 1-2 positive SLNs were retrospectively reviewed from a multi-institutional database. Patients were divided into sentinel lymph node biopsy (SLNB) group and ALND group. Administration of adjuvant chemotherapy and survival were compared between groups. To further verify the results, a meta-analysis was also conducted. RESULTS Among the 1161 enrolled patients, 893 (76.9%) received ALND and 268 (23.1%) underwent SLNB alone. Administration of chemotherapy was comparable between the two groups (91.1% vs. 90.6%, P = 0.798), which was consistent in TM (P = 0.638) and BCS cohort (P = 0.576). After a median follow-up of 36 months, no significant difference was observed between the two groups in recurrence-free survival (P = 0.583) regardless of surgery of breast. During further meta-analysis, 13 out of 4733 relative studies reported the association of axillary surgery and disease-free survival (DFS) or overall survival (OS) in 1-2 positive SLNs patients. Pooled analysis showed no difference in adjusted DFS (HR 0.84, 95% CI 0.70-1.02) or OS (HR 1.02, 95% CI 0.93-1.11) between SLNB and ALND groups. Survival benefit of ALND remained non-significant after restricting the analysis in four studies with patients only receiving BCS, or in three studies with patients only receiving TM. CONCLUSION Further ALND does not impact adjuvant chemotherapy administration or disease outcome in breast cancer patients with 1-2 positive SLNs treated with TM.
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Targeted Therapy of B7 Family Checkpoints as an Innovative Approach to Overcome Cancer Therapy Resistance: A Review from Chemotherapy to Immunotherapy. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113545. [PMID: 35684481 PMCID: PMC9182385 DOI: 10.3390/molecules27113545] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/17/2022]
Abstract
It is estimated that there were 18.1 million cancer cases worldwide in 2018, with about 9 million deaths. Proper diagnosis of cancer is essential for its effective treatment because each type of cancer requires a specific treatment procedure. Cancer therapy includes one or more approaches such as surgery, radiotherapy, chemotherapy, and immunotherapy. In recent years, immunotherapy has received much attention and immune checkpoint molecules have been used to treat several cancers. These molecules are involved in regulating the activity of T lymphocytes. Accumulated evidence shows that targeting immune checkpoint regulators like PD-1/PD-L1 and CTLA-4 are significantly useful in treating cancers. According to studies, these molecules also have pivotal roles in the chemoresistance of cancer cells. Considering these findings, the combination of immunotherapy and chemotherapy can help to treat cancer with a more efficient approach. Among immune checkpoint molecules, the B7 family checkpoints have been studied in various cancer types such as breast cancer, myeloma, and lymphoma. In these cancers, they cause the cells to become resistant to the chemotherapeutic agents. Discovering the exact signaling pathways and selective targeting of these checkpoint molecules may provide a promising avenue to overcome cancer development and therapy resistance. Highlights: (1) The development of resistance to cancer chemotherapy or immunotherapy is the main obstacle to improving the outcome of these anti-cancer therapies. (2) Recent investigations have described the involvement of immune checkpoint molecules in the development of cancer therapy resistance. (3) In the present study, the molecular participation of the B7 immune checkpoint family in anticancer therapies has been highlighted. (4) Targeting these immune checkpoint molecules may be considered an efficient approach to overcoming this obstacle.
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Tinterri C, Gentile D, Gatzemeier W, Sagona A, Barbieri E, Testori A, Errico V, Bottini A, Marrazzo E, Dani C, Dozin B, Boni L, Bruzzi P, Fernandes B, Franceschini D, Spoto R, Torrisi R, Scorsetti M, Santoro A, Canavese G. Preservation of Axillary Lymph Nodes Compared with Complete Dissection in T1-2 Breast Cancer Patients Presenting One or Two Metastatic Sentinel Lymph Nodes: The SINODAR-ONE Multicenter Randomized Clinical Trial. Ann Surg Oncol 2022; 29:5732-5744. [PMID: 35552930 DOI: 10.1245/s10434-022-11866-w] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 04/20/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND The SINODAR-ONE trial is a prospective noninferiority multicenter randomized study aimed at assessing the role of axillary lymph node dissection (ALND) in patients undergoing either breast-conserving surgery or mastectomy for T1-2 breast cancer (BC) and presenting one or two macrometastatic sentinel lymph nodes (SLNs). The endpoints were to evaluate whether SLN biopsy (SLNB) only was associated with worsening of the prognosis compared with ALND in terms of overall survival (OS) and relapse. METHODS Patients were randomly assigned (1:1 ratio) to either removal of ≥ 10 axillary level I/II non-SLNs followed by adjuvant therapy (standard arm) or no further axillary treatment (experimental arm). RESULTS The trial started in April 2015 and ceased in April 2020, involving 889 patients. Median follow-up was 34.0 months. There were eight deaths (ALND, 4; SNLB only, 4), with 5-year cumulative mortality of 5.8% and 2.1% in the standard and experimental arm, respectively (p = 0.984). There were 26 recurrences (ALND 11; SNLB only, 15), with 5-year cumulative incidence of recurrence of 6.9% and 3.3% in the standard and experimental arm, respectively (p = 0.444). Only one axillary lymph node recurrence was observed in each arm. The 5-year OS rates were 98.9% and 98.8%, in the ALND and SNLB-only arm, respectively (p = 0.936). CONCLUSIONS The 3-year survival and relapse rates of T1-2 BC patients with one or two macrometastatic SLNs treated with SLNB only, and adjuvant therapy, were not inferior to those of patients treated with ALND. These results do not support the use of routine ALND.
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Affiliation(s)
- Corrado Tinterri
- Breast Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Damiano Gentile
- Breast Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
| | | | - Andrea Sagona
- Breast Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Erika Barbieri
- Breast Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alberto Testori
- Breast Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Valentina Errico
- Breast Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alberto Bottini
- Breast Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | - Carla Dani
- Department of Epidemiology, Biostatistics and Clinical Trials, IRCCS S. Martino, IST, Genoa, Italy
| | - Beatrice Dozin
- Department of Epidemiology, Biostatistics and Clinical Trials, IRCCS S. Martino, IST, Genoa, Italy
| | - Luca Boni
- Department of Epidemiology, Biostatistics and Clinical Trials, IRCCS S. Martino, IST, Genoa, Italy
| | - Paolo Bruzzi
- Department of Epidemiology, Biostatistics and Clinical Trials, IRCCS S. Martino, IST, Genoa, Italy
| | - Bethania Fernandes
- Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Davide Franceschini
- Radiotherapy and Radiosurgery Department, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Ruggero Spoto
- Radiotherapy and Radiosurgery Department, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Rosalba Torrisi
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Marta Scorsetti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.,Radiotherapy and Radiosurgery Department, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Giuseppe Canavese
- Breast Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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Wang S, Zhang X, Ning H, Dong S, Wang G, Sun R. B7 homolog 3 induces lung metastasis of breast cancer through Raf/MEK/ERK axis. Breast Cancer Res Treat 2022; 193:405-416. [PMID: 35312883 DOI: 10.1007/s10549-022-06520-8] [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] [Received: 07/31/2021] [Accepted: 01/05/2022] [Indexed: 12/22/2022]
Abstract
PURPOSE The essential action of B7 homolog 3 (B7-H3) in different diseases and cancers has been documented. We here focused on its role in breast cancer through the Raf/MEK/ERK axis regarding lung metastasis. METHODS Expression pattern of B7-H3 was determined in breast cancer tissues and cells with its correlation with prognosis analyzed. Then, through transfection of lentivirus vector expressing B7-H3-shRNA, overexpression vector of B7-H3 (B7-H3-LV), U0126 (small molecule inhibitor of MEK), or PD98059 (small molecule inhibitor of ERK), the in vitro and in vivo effects of B7-H3 in breast cancer cell biological processes, and lung metastasis were analyzed in relation to the Raf/MEK/ERK axis. RESULTS We discovered elevated B7-H3 in breast cancer and its elevation associated with poor prognosis. B7-H3 promoted the malignant properties of breast cancer cells, accompanied with increased N-cadherin and vimentin and reduced E-cadherin. Additionally, overexpression of B7-H3 accelerated the lung metastasis in breast cancer in vivo. All the above promoting action of B7-H3 was achieved through activation of the Raf/MEK/ERK signaling pathway. CONCLUSION Taken together, B7-H3 can promote lung metastasis in breast cancer through activation of the Raf/MEK/ERK axis.
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Affiliation(s)
- Shuai Wang
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, No. 2428, Yuhe Road, Weifang, 261031, Shandong Province, China
| | - Xinyan Zhang
- Department of Intervention, The Affiliated Weihai Second Municipal Hospital of Qingdao University, Weihai, 264200, China
| | - Houfa Ning
- School of Medical Imaging, Weifang Medical University, No. 7166, Baotong West Street, Weifang, 261053, Shandong Province, China
| | - Senyi Dong
- School of Medical Imaging, Weifang Medical University, No. 7166, Baotong West Street, Weifang, 261053, Shandong Province, China
| | - Guangzhi Wang
- School of Medical Imaging, Weifang Medical University, No. 7166, Baotong West Street, Weifang, 261053, Shandong Province, China.
| | - Ruimei Sun
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, No. 2428, Yuhe Road, Weifang, 261031, Shandong Province, China.
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Feng R, Chen Y, Liu Y, Zhou Q, Zhang W. The role of B7-H3 in tumors and its potential in clinical application. Int Immunopharmacol 2021; 101:108153. [PMID: 34678689 DOI: 10.1016/j.intimp.2021.108153] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023]
Abstract
B7-H3 (CD276 molecule) is an immune checkpoint from the B7 family of molecules that acts more as a co-inhibitory molecule to promote tumor progression. It is abnormally expressed on tumor cells and can be induced to express on antigen-presenting cells (APCs) including dendritic cells (DCs) and macrophages. In the tumor microenvironment (TME), B7-H3 promotes tumor progression by impairing T cell response, promoting the polarization of tumor-associated macrophages (TAMs) to M2, inhibiting the function of DCs, and promoting the migration and invasion of cancer-associated fibroblasts (CAFs). In addition, through non-immunological functions, B7-H3 promotes tumor cell proliferation, invasion, metastasis, resistance, angiogenesis, and metabolism, or in the form of exosomes to promote tumor progression. In this process, microRNAs can regulate the expression of B7-H3. B7-H3 may serve as a potential biomarker for tumor diagnosis and a marker of poor prognosis. Immunotherapy targeting B7-H3 and the combination of B7-H3 and other immune checkpoints have shown certain efficacy. In this review, we summarized the basic characteristics of B7-H3 and its mechanism to promote tumor progression by inducing immunosuppression and non-immunological functions, as well as the potential clinical applications of B7-H3 and immunotherapy based on B7-H3.
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Affiliation(s)
- Ranran Feng
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Andrology, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
| | - Yong Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ying Liu
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Qing Zhou
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Wenling Zhang
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
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Masoumi E, Tahaghoghi-Hajghorbani S, Jafarzadeh L, Sanaei MJ, Pourbagheri-Sigaroodi A, Bashash D. The application of immune checkpoint blockade in breast cancer and the emerging role of nanoparticle. J Control Release 2021; 340:168-187. [PMID: 34743998 DOI: 10.1016/j.jconrel.2021.10.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022]
Abstract
Breast cancer is the most common malignancy in the female population with a high mortality rate. Despite the satisfying depth of studies evaluating the contributory role of immune checkpoints in this malignancy, few articles have reviewed the pros and cons of immune checkpoint blockades (ICBs). In the current review, we provide an overview of immune-related inhibitory molecules and also discuss the original data obtained from international research laboratories on the aberrant expression of T and non-T cell-associated immune checkpoints in breast cancer. Then, we especially focus on recent studies that utilized ICBs as the treatment strategy in breast cancer and provide their efficiency reports. As there are always costs and benefits, we discuss the limitations and challenges toward ICB therapy such as adverse events and drug resistance. In the last section, we allocate an overview of the recent data concerning the application of nanoparticle systems for cancer immunotherapy and propose that nano-based ICB approaches may overcome the challenges related to ICB therapy in breast cancer. In conclusion, it seems it is time for nanoscience to more rapidly move forward into clinical trials and illuminates the breast cancer treatment area with its potent features for the target delivery of ICBs.
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Affiliation(s)
- Elham Masoumi
- Department of Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran; Student Research Committee, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Sahar Tahaghoghi-Hajghorbani
- Microbiology and Virology Research Center, Qaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Leila Jafarzadeh
- Department of Laboratory Science, Sirjan Faculty of Medical Science, Sirjan, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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31
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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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Kim NI, Park MH, Lee JS. Associations of B7-H3 and B7-H4 Expression in Ductal Carcinoma In Situ of the Breast With Clinicopathologic Features and T-Cell Infiltration. Appl Immunohistochem Mol Morphol 2021; 28:767-775. [PMID: 31714284 DOI: 10.1097/pai.0000000000000817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
B7-H3 and B7-H4 play an inhibitory role in T-cell function by limiting proliferation and cytokine production. Information about B7-H3 and B7-H4 expression in ductal carcinoma in situ (DCIS) remains uncertain. The objective of this study was to evaluate the expression levels of B7-H3 and B7-H4 in DCIS and their associations with clinicopathologic features and T-cell infiltration. B7-H3 and B7-H4 mRNA and protein expression levels in 8 pairs of DCIS tissues and matched normal adjacent tissues were examined by RNAscope in situ hybridization and immunohistochemistry analysis. Immunohistochemical staining of B7-H3, B7-H4, CD3, and CD8 was performed for 79 DCIS samples using tissue microarray. RNAscope in situ hybridization and immunohistochemistry analysis revealed that expression levels of B7-H3 and B7-H4 in DCIS tissues were higher than those in corresponding normal tissues. B7-H3 and B7-H4 mRNA and protein appeared to be mainly expressed in DCIS carcinoma cells. High B7-H3 and B7-H4 expression was observed in 58 (73.4%) and 62 (78.5%) cases with DCIS, respectively. High B7-H3 expression was significantly associated with high-nuclear grade and presence of comedo-type necrosis (both P<0.05). B7-H3 expression in HR/HER2 subtype was higher than that in HR/HER2 subtype (P<0.05). B7-H3 and B7-H4 expression levels were negatively related to the density of CD3 and CD8 T-cell infiltrates. B7-H3 and B7-H4 may play an important role in immune surveillance mechanisms of DCIS. They might be useful targets to develop immune-based therapy to alter or prevent DCIS progression.
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Affiliation(s)
| | - Min Ho Park
- Surgery, Chonnam National University Medical School, Gwangju, South Korea
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Zhou Q, Li K, Lai Y, Yao K, Wang Q, Zhan X, Peng S, Cai W, Yao W, Zang X, Xu K, Huang J, Huang H. B7 score and T cell infiltration stratify immune status in prostate cancer. J Immunother Cancer 2021; 9:jitc-2021-002455. [PMID: 34417325 PMCID: PMC8381330 DOI: 10.1136/jitc-2021-002455] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Although immune checkpoint inhibitors (ICIs), especially programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis blockers, exhibit prominent antitumor effects against numerous malignancies, their benefit for patients with prostate cancer (PCa) has been somewhat marginal. This study aimed to assess the feasibility of B7-H3 or HHLA2 as alternative immunotherapeutic targets in PCa. METHODS Immunohistochemistry was performed to evaluate the expression pattern of PD-L1, B7-H3 and HHLA2 and the infiltration of CD8+ and Foxp3+ lymphocytes in 239 PCa tissues from two independent cohorts. The correlations between B7-H3 and HHLA2 and clinicopathological features, including the presence of CD8+ and Foxp3+ tumor-infiltrating lymphocytes (TILs), were explored. RESULTS HHLA2 expression was much higher than PD-L1 expression but lower than B7-H3 expression in PCa tissues. High expression of both B7-H3 and HHLA2 was significantly associated with higher Gleason score and tumor stage, lymph node metastasis and dismal overall survival (OS) and cancer-specific survival (CSS). Moreover, a high B7 score, defined as high B7-H3 expression and/or high HHLA2 expression, was an independent prognostic predictor for PCa. Of note, a high B7 score was negatively correlated with CD8+ TILs. Importantly, a new immune classification, based on the B7 score and CD8+ TILs, successfully stratified OS and CSS in PCa. CONCLUSIONS Both B7-H3 and HHLA2 have a critical impact on the immunosuppressive microenvironment, and the B7 score could be used as an independent prognostic factor for PCa. The B7 score combined with CD8+ TILs could be used as a new immune classification to stratify the risk of death, especially cancer-related death, for patients with PCa. These findings may provide insights that could improve response to immune-related comprehensive therapy for PCa in the future.
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Affiliation(s)
- Qianghua Zhou
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Kaiwen Li
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yiming Lai
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Kai Yao
- Department of urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Qiong Wang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiangyu Zhan
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shirong Peng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Wenli Cai
- Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Wei Yao
- Department of Oncology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Xingxing Zang
- Department of Oncology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Kewei Xu
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China .,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jian Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China .,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Hai Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China .,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.,Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.,Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, china
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Huang L, Zhou Y, Sun Q, Cao L, Zhang X. Evaluation of the role of soluble B7-H3 in association with membrane B7-H3 expression in gastric adenocarcinoma. Cancer Biomark 2021; 33:123-129. [PMID: 34459388 DOI: 10.3233/cbm-210178] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND OBJECTIVE Gastric adenocarcinoma (GAC) is one of the most common malignancies. Increasing data have indicated a correlation between soluble B7-H3 (sB7-H3) levels and tumor malignancies. In this study, we aim to investigate the level of soluble B7-H3 in serum of GAC patients. Further, we analyze the correlation between sB7-H3 level and tissue B7-H3 expression and explore the clinical evaluation value of sB7-H3 associated with pathological characteristics and prognosis of GAC patients. METHODS One hundred and twenty-eight serum and tissue samples of GAC 20 serum and tissue samples of gastritis patients and 77 serum, 5 tissue samples of healthy controls were collected. The serum levels of sB7-H3 were detected by Enzyme-linked immunosorbent assay (ELISA), while the expression of membrane B7-H3 (mB7-H3) and Ki67 were evaluated by immunohistochemistry. The correlation between sB7-H3 and mB7-H3, sB7-H3 and Ki67, sB7-H3 or mB7-H3 and clinical features were analyzed by Pearson's Chi-square test. RESULTS Both serum level of sB7-H3 and tissue B7-H3 of GAC patients were significantly higher than those of gastritis patients and healthy controls. sB7-H3 level was correlated with total B7-H3 expression in tissues (r= 0.2801, P= 0.0014). Notably, the concentration of sB7-H3 was correlated with its expression of membrane form in tumor cells (r= 0.3251, P= 0.002) while not in stromal cells (r= 0.07676, P= 0.3891). Moreover, the levels of sB7-H3 in patients with TNM stage III/IV or with Infiltration depth T3/T4 or with lymph node metastasis were significantly higher than those of patients with TNM stage I/II (P= 0.0020) or with Infiltration depth T1/T2 (P= 0.0169) or with no lymph node metastasis (P= 0.0086). Tumor B7-H3 score, but not stromal B7-H3 score, in patients with TNM stage III/IV or with lymph node metastasis was significantly higher than those with TNM stage I/II (P= 0.0150) or with no lymph node metastasis (P= 0.182). CONCLUSIONS Soluble B7-H3 level may reflect the tissue B7-H3 expression on tumor cells of GAC tissues. Elevated level of sB7-H3 in serum suggests poor clinical pathological characteristics of GAC patients.
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Affiliation(s)
- Lili Huang
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.,Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yan Zhou
- The AoYang Cancer Research Institute of Jiangsu University, Zhangjiagang, Suzhou, Jiangsu, China.,Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Qiuwei Sun
- The AoYang Cancer Research Institute of Jiangsu University, Zhangjiagang, Suzhou, Jiangsu, China
| | - Lei Cao
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Suzhou, Jiangsu, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Suzhou, Jiangsu, China
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Zhang Q, Zong L, Zhang H, Xie W, Yang F, Sun W, Cui B, Zhang Y. Expression of B7-H3 Correlates with PD-L1 and Poor Prognosis in Patients with Cervical Cancer. Onco Targets Ther 2021; 14:4275-4283. [PMID: 34326649 PMCID: PMC8315807 DOI: 10.2147/ott.s318082] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 06/28/2021] [Indexed: 12/14/2022] Open
Abstract
Purpose The purpose of this study was to investigate B7 homolog 3 (B7-H3) expression patterns and define its associations with programmed cell-death ligand 1 (PD-L1), pathological features, and survival in patients with cervical cancer. Patients and Methods Immunohistochemical staining was used to investigate B7-H3 and PD-L1 expression in tissue microarrays from 552 patients with stage IB1 and IIA1 cervical cancer, including 406 with squamous cell carcinoma and 146 with endocervical adenocarcinoma. Results B7-H3 was expressed in the tumor cells (TCs) of 32.1% of the samples as well as in the stromal cells of 92.9% of the specimens. B7-H3 was co-expressed with PD-L1 in 21.0% of the samples, while only one or the other was expressed in 41.7% of the samples. B7-H3 expression in TCs was more frequent in squamous cell carcinoma, PD-L1-positive samples, and tissues from patients with lymph node metastasis; moreover, its expression was an independent predictor of shorter survival. Conclusion B7-H3 positivity in TCs is a promising prognostic biomarker, and targeting B7-H3 alone or in combination with PD-1/PD-L1 may be a potential immunotherapeutic strategy for patients with cervical cancer.
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Affiliation(s)
- Qianqian Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.,Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, People's Republic of China
| | - Liju Zong
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Hui Zhang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, People's Republic of China
| | - Wei Xie
- Department of Emergency, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, People's Republic of China
| | - Fan Yang
- Department of Pathology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, People's Republic of China
| | - Wenwen Sun
- Department of Pathology, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, People's Republic of China
| | - Baoxia Cui
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China
| | - Youzhong Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China
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Zhou WT, Jin WL. B7-H3/CD276: An Emerging Cancer Immunotherapy. Front Immunol 2021; 12:701006. [PMID: 34349762 PMCID: PMC8326801 DOI: 10.3389/fimmu.2021.701006] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/05/2021] [Indexed: 12/18/2022] Open
Abstract
Immunotherapy aiming at suppressing tumor development by relying on modifying or strengthening the immune system prevails among cancer treatments and points out a new direction for cancer therapy. B7 homolog 3 protein (B7-H3, also known as CD276), a newly identified immunoregulatory protein member of the B7 family, is an attractive and promising target for cancer immunotherapy because it is overexpressed in tumor tissues while showing limited expression in normal tissues and participating in tumor microenvironment (TME) shaping and development. Thus far, numerous B7-H3-based immunotherapy strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Herein, we present the expression and biological function of B7-H3 in distinct cancer and normal cells, as well as B7-H3-mediated signal pathways in cancer cells and B7-H3-based tumor immunotherapy strategies. This review provides a comprehensive overview that encompasses B7-H3’s role in TME to its potential as a target in cancer immunotherapy.
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Affiliation(s)
- Wu-Tong Zhou
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Lin Jin
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China.,Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, China
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37
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Zhou Y, Zhou H, Shi J, Guan A, Zhu Y, Hou Z, Li R. Decreased m6A Modification of CD34/CD276(B7-H3) Leads to Immune Escape in Colon Cancer. Front Cell Dev Biol 2021; 9:715674. [PMID: 34307389 PMCID: PMC8297592 DOI: 10.3389/fcell.2021.715674] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 06/21/2021] [Indexed: 12/21/2022] Open
Abstract
Previous studies have reported that m6a modification promotes tumor immune escape by affecting tumor microenvironment (TME). Due to the complexity of TME, a single biomarker is insufficient to describe the complex biological characteristics of tumor and its microenvironment. Therefore, it is more meaningful to explore a group of effective biomarkers reflecting different characteristics of cancer to evaluate the biological characteristics of solid tumors. Here, the immune gene CD34/CD276 with different m6A peak was obtained by m6A sequencing (MeRIP-seq) of colon cancer (CRC)clinical samples and combined with MsIgDB database, which was used to perform cluster analysis on TCGA-COAD level 3 data. The CD34/CD276 as a molecular marker for CRC prognosis was confirmed by survival analysis and immunohistochemical assay. Further bioinformatics analysis was carried out to analyze the molecular mechanism of CD34/CD276 affecting the TME through m6a-dependent down-regulation and ultimately promoting immune escape of CRC.
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Affiliation(s)
- Yiran Zhou
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, First Department of General Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Haodong Zhou
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, First Department of General Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jianlin Shi
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Department of Thoracic Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Aoran Guan
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, First Department of General Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yankun Zhu
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, First Department of General Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zongliu Hou
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China
| | - Ruhong Li
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, First Department of General Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China
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38
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Ying H, Zhang X, Duan Y, Lao M, Xu J, Yang H, Liang T, Bai X. Non-cytomembrane PD-L1: An atypical target for cancer. Pharmacol Res 2021; 170:105741. [PMID: 34174446 DOI: 10.1016/j.phrs.2021.105741] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 02/07/2023]
Abstract
Programmed death ligand 1 (PD-L1) has conventionally been considered as a type I transmembrane protein that can interact with its receptor, programmed cell death 1 (PD-1), thus inducing T cell deactivation and immune escape. However, targeting the PD-1/PD-L1 axis has achieved adequate clinical responses in very few specific malignancies. Recent studies have explored the extracellularly and subcellularly located PD-L1, namely, nuclear PD-L1 (nPD-L1), cytoplasmic PD-L1 (cPD-L1), soluble PD-L1 (sPD-L1), and extracellular vesicle PD-L1 (EV PD-L1), which might shed light on the resistance to anti-PD1/PDL1 therapy. In this review, we summarize the four atypical localizations of PD-L1 with a focus on their novel functions, such as gene transcription regulation, therapeutic efficacy prediction, and resistance to various cancer therapies. Additionally, we highlight that non-cytomembrane PD-L1s are of significant cancer diagnostic value and are promising therapeutic targets to treat cancer.
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Affiliation(s)
- Honggang Ying
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou 310003, Zhejiang, China
| | - Xiaozhen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou 310003, Zhejiang, China
| | - Yi Duan
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou 310003, Zhejiang, China
| | - Mengyi Lao
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou 310003, Zhejiang, China
| | - Jian Xu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou 310003, Zhejiang, China
| | - Hanshen Yang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou 310003, Zhejiang, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou 310003, Zhejiang, China.
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou 310003, Zhejiang, China.
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Omilian AR, Sheng H, Hong CC, Bandera EV, Khoury T, Ambrosone CB, Yao S. Multiplexed digital spatial profiling of invasive breast tumors from Black and White women. Mol Oncol 2021; 16:54-68. [PMID: 34018684 PMCID: PMC8732343 DOI: 10.1002/1878-0261.13017] [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: 11/02/2020] [Revised: 04/19/2021] [Accepted: 05/18/2021] [Indexed: 12/17/2022] Open
Abstract
The NanoString GeoMx digital spatial profiling is a new multiplexed platform that quantifies the abundance of tumor‐ and immune‐related proteins in a spatially resolved manner. We performed DSP for the simultaneous assessment of 52 analytes within spatially resolved tissue compartments defined by pan‐cytokeratin expression. We compared protein targets between 94 African American/Black and 65 European American/White cases, tumor and stromal tissue compartments, estrogen receptor alpha (ER)‐positive and ER‐negative cases, and explored potential biomarkers of survival. Of 33 analytes with robust signal for analysis, results were highly replicable. For a subset of markers, correlative analyses between DSP analytes and traditional immunohistochemistry scores revealed moderate to very strong associations between the two platforms. Similarly, DSP analytes and gene expression scores were concordant for 21 of 25 markers with overlap between the two datasets. Several analytes varied by ER status, and across the 25 immune markers surveyed, 14 had a significant inverse association with ER expression. B7 homolog 3 (B7‐H3; encoded by CD276) was the only analyte to show a significant difference by race, being lower in both the tumor and stromal compartments in Black women. DSP markers that were associated with survival included CD8, CD25, CD56, CD127, EpCAM, ER, Ki‐67, and STING. We conclude that DSP is an efficient tool for screening tumor‐ and immune‐related markers in a simultaneous fashion and yields results that are concordant with established immune profiling assays. DSP immune analytes were inversely associated with ER expression, in agreement with a substantial body of previous work that documents higher immune infiltration in ER‐negative breast cancers. This technology revealed that scores of the B7‐H3 protein were significantly lower in breast cancers from Black women compared with White women, an intriguing finding that requires replication in independent and racially diverse female populations.
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Affiliation(s)
- Angela R Omilian
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Haiyang Sheng
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,Department of Biostatistics, The State University of New York at Buffalo, NY, USA
| | - Chi-Chen Hong
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Elisa V Bandera
- Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ, USA.,Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Thaer Khoury
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christine B Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Song Yao
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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Michelakos T, Kontos F, Barakat O, Maggs L, Schwab JH, Ferrone CR, Ferrone S. B7-H3 targeted antibody-based immunotherapy of malignant diseases. Expert Opin Biol Ther 2021; 21:587-602. [PMID: 33301369 PMCID: PMC8087627 DOI: 10.1080/14712598.2021.1862791] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023]
Abstract
Introduction: Recent advances in immuno-oncology and bioengineering have rekindled the interest in monoclonal antibody (mAb)-based immunotherapies for malignancies. Crucial for their success is the identification of tumor antigens (TAs) that can serve as targets. B7-H3, a member of the B7 ligand family, represents such a TA. Although its exact functions and receptor(s) remain unclear, B7-H3 has predominantly a pro-tumorigenic effect mainly by suppressing the anti-tumor functions of T-cells.Areas covered: Initially we present a historical perspective on TA-specific antibodies for diagnosis and treatment of malignancies. Following a description of the TA requirements to be an attractive antibody-based immunotherapy target, we show that B7-H3 fulfills these criteria. We discuss its structure and functions. In a review and pooled analysis, we describe the limited B7-H3 expression in normal tissues and estimate B7-H3 expression frequency in tumors, tumor-associated vasculature and cancer initiating cells (CICs). Lastly, we discuss the association of B7-H3 expression in tumors with poor prognosis.Expert opinion: B7-H3 is an attractive target for mAb-based cancer immunotherapy. B7-H3-targeting strategies are expected to be highly effective and - importantly - safe. To fully exploit the diagnostic and therapeutic potential of B7-H3, its expression in pre-malignant lesions, serum, metastases, and CICs requires further investigation.
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Affiliation(s)
- Theodoros Michelakos
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Filippos Kontos
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Omar Barakat
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Luke Maggs
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Joseph H Schwab
- Department of Orthopaedic Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
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Li ZY, Wang JT, Chen G, Shan ZG, Wang TT, Shen Y, Chen J, Yan ZB, Peng LS, Mao FY, Teng YS, Liu JS, Zhou YY, Zhao YL, Zhuang Y. Expression, regulation and clinical significance of B7-H3 on neutrophils in human gastric cancer. Clin Immunol 2021; 227:108753. [PMID: 33945871 DOI: 10.1016/j.clim.2021.108753] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/27/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022]
Abstract
Neutrophils are conspicuous components of gastric cancer (GC) tumors, increasing with tumor progression and poor patient survival. However, the phenotype, regulation and clinical relevance of neutrophils in human GC are presently unknown. Most intratumoral neutrophils showed an activated CD54+ phenotype and expressed high level B7-H3. Tumor tissue culture supernatants from GC patients induced the expression of CD54 and B7-H3 on neutrophils in time-dependent and dose-dependent manners. Locally enriched CD54+ neutrophils and B7-H3+ neutrophils positively correlated with increased granulocyte-macrophage colony stimulating factor (GM-CSF) detection ex vivo; and in vitro GM-CSF induced the expression of CD54 and B7-H3 on neutrophils in both time-dependent and dose-dependent manners. Furthermore, GC tumor-derived GM-CSF activated neutrophils and induced neutrophil B7-H3 expression via JAK-STAT3 signaling pathway activation. Finally, intratumoral B7-H3+ neutrophils increased with tumor progression and independently predicted reduced overall survival. Collectively, these results suggest B7-H3+ neutrophils to be potential biomarkers in GC.
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Affiliation(s)
- Zheng-Yan Li
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Jin-Tao Wang
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Gang Chen
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zhi-Guo Shan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ting-Ting Wang
- Chongqing Key Research Laboratory for Drug Metabolism, Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Yang Shen
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jun Chen
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zong-Bao Yan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Liu-Sheng Peng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Fang-Yuan Mao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yong-Sheng Teng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Jin-Shan Liu
- Department of General Surgery, Qijiang Hospital of the First Affiliated Hospital of Chongqing Medical University, Qijiang, Chongqing, China
| | - Yuan-Yuan Zhou
- Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China.
| | - Yong-Liang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
| | - Yuan Zhuang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China; Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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Liu S, Liang J, Liu Z, Zhang C, Wang Y, Watson AH, Zhou C, Zhang F, Wu K, Zhang F, Lu Y, Wang X. The Role of CD276 in Cancers. Front Oncol 2021; 11:654684. [PMID: 33842369 PMCID: PMC8032984 DOI: 10.3389/fonc.2021.654684] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/02/2021] [Indexed: 02/05/2023] Open
Abstract
Objective Aberrant expression of the immune checkpoint molecule, CD276, also known as B7-H3, is associated with tumorigenesis. In this review, we aim to comprehensively describe the role of CD276 in malignancies and its potential therapeutic effect. Data Sources Database including PubMed, EMbase, Cochrane Library, CNKI, and Clinical Trails.gov were searched for eligible studies and reviews. Study selection: Original studies and review articles on the topic of CD276 in tumors were retrieved. Results CD276 is an immune checkpoint molecule in the epithelial mesenchymal transition (EMT) pathway. In this review, we evaluated the available evidence on the expression and regulation of CD276. We also assessed the role of CD276 within the immune micro-environment, effect on tumor progression, and the potential therapeutic effect of CD276 targeted therapy for malignancies. Conclusion CD276 plays an essential role in cell proliferation, invasion, and migration in malignancies. Results from most recent studies indicate CD276 could be a promising therapeutic target for malignant tumors.
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Affiliation(s)
- Shengzhuo Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Jiayu Liang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhihong Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Chi Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Wang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Alice Helen Watson
- Clinical Science and Services, Royal Veterinary College, University of London, London, United Kingdom
| | - Chuan Zhou
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Fan Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Kan Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Fuxun Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Yiping Lu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Xianding Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
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Mast cell proliferation in the cerebrospinal fluid after intraventricular administration of anti-B7H3 immunotherapy. Cancer Immunol Immunother 2021; 70:2411-2414. [PMID: 33533945 PMCID: PMC8289752 DOI: 10.1007/s00262-020-02824-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/07/2020] [Indexed: 11/28/2022]
Abstract
Omburtamab is a B7H3-specific murine monoclonal antibody. B7H3 (CD 276) is a member of the B7 family of immune checkpoint co-inhibitory receptors overexpressed on many human malignancies. Radioimmunotherapy with 124I- or 131I-omburtamab administered in the cerebrospinal fluid (CSF), intraperitoneal or intratumoral cavity is currently under investigation for the treatment of CNS malignancies. The immunologic effects of anti-B7H3 therapy are not fully elucidated. A 6-year-old male was diagnosed with metastates of neuroblastoma to the received intraventricular 131I-omburtamab on an IRB-approved protocol. A treatment cycle consisted of a 2 mCi dosimetry dose and a 50 mCi treatment dose. Dosimetry by serial imaging, pharmacokinetics and safety were investigated. Clinical status, magnetic resonance imaging, CSF cell count and cytology were evaluated pre- and post-131I-omburtamab at 5 and 26 weeks. The patient did well with cycle 1. Three hours after the dosimetry dose of cycle 2, he developed a fever (39 °C), chills and headache. Blood and CSF samples were sent for culture. CSF was notable for nucleated cell pleocytosis with profound mast cell proliferation consistent with chemical meningitis. He was treated with supportive care; symptoms resolved over 48 h. Further therapy with 131I-omburtamab was electively discontinued. CSF cell count 5 weeks later demonstrated resolution of CSF pleocytosis. Local–regional administration of intraventricular 131I-omburtamab targeting B7H3 can result in a profound nucleated CSF pleocytosis with mastocytosis consistent with an acute allergic reaction.
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Epithelial splicing regulatory protein 1 and 2 (ESRP1 and ESRP2) upregulation predicts poor prognosis in prostate cancer. BMC Cancer 2020; 20:1220. [PMID: 33339518 PMCID: PMC7749503 DOI: 10.1186/s12885-020-07682-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 11/23/2020] [Indexed: 01/26/2023] Open
Abstract
Background Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2) regulate alternative splicing events of various pre-mRNAs. Some of these targets play a role in cancer-associated processes, including cytoskeleton reorganization and DNA-repair processes. This study was undertaken to estimate the impact of ESRP1 and ESRP2 alterations on prostate cancer patient prognosis. Methods A tissue microarray made from 17,747 individual cancer samples with comprehensive, pathological, clinical and molecular data was analyzed by immunohistochemistry for ESRP1 and ESRP2. Results Nuclear staining for ESRP1 was seen in 38.6% (36.0% low, 2.6% high) of 12,140 interpretable cancers and in 41.9% (36.4% low, 5.3% high) of 12,962 interpretable cancers for ESRP2. Nuclear protein expression was linked to advanced tumor stage, high Gleason score, presence of lymph node metastasis, early biochemical recurrence, and ERG-positive cancers (p < 0.0001 each). Expression of ESRPs was significantly linked to 11 (ESRP1)/9 (ESRP2) of 11 analyzed deletions in all cancers and to 8 (ESRP1)/9 (ESRP2) of 11 deletions in ERG-negative cancers portending a link to genomic instability. Combined ESRPs expression analysis suggested an additive effect and showed the worst prognosis for cancers with high ESRP1 and ESRP2 expression. Multivariate analyses revealed that the prognostic impact of ESRP1, ESRP2 and combined ESRP1/ESRP2 expression was independent of all established pre- and postoperative prognostic features. Conclusions Our data show a striking link between nuclear ESRP expression and adverse features in prostate cancer and identifies expression of ESRP1 and/or ESRP2 as independent prognostic markers with a potential for routine application.
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Lu Z, Zhao ZX, Cheng P, Huang F, Guan X, Zhang MG, Chen HP, Liu Z, Jiang Z, Zheng ZX, Zou SM, Wang XS. B7-H3 immune checkpoint expression is a poor prognostic factor in colorectal carcinoma. Mod Pathol 2020; 33:2330-2340. [PMID: 32514163 DOI: 10.1038/s41379-020-0587-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/24/2020] [Accepted: 05/25/2020] [Indexed: 12/24/2022]
Abstract
Although PD-1/PD-L1 immunotherapy has been used successfully in treating many cancers, metastatic colorectal cancer (CRC) patients are not as responsive. B7-H3 is a promising target for immunotherapy and we found it to have the highest expression among B7-CD28 family members in CRC. Thus, the aim of the present study was to investigate B7-H3 expression in a large CRC cohort. B7-H3, B7-H4, and PD-L1 protein levels and differential lymphocyte infiltration were evaluated in tissue microarrays from 805 primary tumors and matched metastases. The relationships between immune markers, patient characteristics, and survival outcomes were determined. B7-H3 (50.9%) was detected in more primary tumors than B7-H4 (29.1%) or PD-L1 (29.2%), and elevated B7-H3 expression was associated with advanced overall stage. Co-expression of B7-H3 only with B7-H4 or PD-L1 was infrequent in primary tumors (6.3%, 5.7%, respectively). Moreover, B7-H3 in primary tumors was positively correlated with their respective expression at metastatic sites (ρ = 0.631; p < 0.001). No significant relationships between B7-H4 and PD-L1 and survival were observed; however, B7-H3 overexpression in primary tumors was significantly related to decreased disease-free survival. A positive relationship between B7-H3 expression and high density CD45RO T cell was observed in primary tumors, whereas B7-H4 and PD-L1 overexpression were related to CD3 T-cell infiltration. In conclusion, compared with B7-H4 and PD-L1, B7-H3 expression exhibited a higher prevalence and was significantly related to aggressiveness, worse prognosis and CD45RO T-cell infiltration in primary tumors. Further exploration of this potential target of immunotherapy in CRC patients is warranted.
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Affiliation(s)
- Zhao Lu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhi-Xun Zhao
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pu Cheng
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fei Huang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xu Guan
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ming-Guang Zhang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hai-Peng Chen
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zheng Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zheng Jiang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhao-Xu Zheng
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Shuang-Mei Zou
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Xi-Shan Wang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Xiong D, Wang Y, You M. A gene expression signature of TREM2 hi macrophages and γδ T cells predicts immunotherapy response. Nat Commun 2020; 11:5084. [PMID: 33033253 PMCID: PMC7545100 DOI: 10.1038/s41467-020-18546-x] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
Identifying factors underlying resistance to immune checkpoint therapy (ICT) is still challenging. Most cancer patients do not respond to ICT and the availability of the predictive biomarkers is limited. Here, we re-analyze a publicly available single-cell RNA sequencing (scRNA-seq) dataset of melanoma samples of patients subjected to ICT and identify a subset of macrophages overexpressing TREM2 and a subset of gammadelta T cells that are both overrepresented in the non-responding tumors. In addition, the percentage of a B cell subset is significantly lower in the non-responders. The presence of these immune cell subtypes is corroborated in other publicly available scRNA-seq datasets. The analyses of bulk RNA-seq datasets of the melanoma samples identify and validate a signature - ImmuneCells.Sig - enriched with the genes characteristic of the above immune cell subsets to predict response to immunotherapy. ImmuneCells.Sig could represent a valuable tool for clinical decision making in patients receiving immunotherapy.
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Affiliation(s)
- Donghai Xiong
- Center for Disease Prevention Research and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Yian Wang
- Center for Disease Prevention Research and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Ming You
- Center for Disease Prevention Research and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
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Bonk S, Tasdelen P, Kluth M, Hube-Magg C, Makrypidi-Fraune G, Möller K, Höflmayer D, Dwertmann Rico S, Büscheck F, Minner S, Heinzer H, Graefen M, Hinsch A, Luebke AM, Dum D, Uhlig R, Schlomm T, Sauter G, Simon R, Weidemann SA. High B7-H3 expression is linked to increased risk of prostate cancer progression. Pathol Int 2020; 70:733-742. [PMID: 32776718 DOI: 10.1111/pin.12999] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/08/2020] [Accepted: 07/14/2020] [Indexed: 12/24/2022]
Abstract
B7-H3 is a member of the B7 superfamily of immune checkpoint molecules. B7-H3 up regulation has been linked to cancer development and progression in many tumors including prostate cancer. To clarify the potential utility of B7-H3 as a prognostic biomarker, B7-H3 expression was analyzed by immunohistochemistry in more than 17 000 prostate cancers. Normal prostatic glands were largely B7-H3 negative, while membranous B7-H3 immunostaining was seen in 47.0% of analyzed cancers. B7-H3 immunostaining was weak in 12.3%, moderate in 21.1% and strong in 13.5% of cases. High B7-H3 expression was associated with pT, Gleason score, lymph node metastasis, high Ki67 labeling index and early prostate-specific antigen recurrence (P < 0.0001 each). High B7-H3 expression was also linked to high androgen receptor expression and TMPRSS2:V-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusions (P < 0.0001 each). Multivariate analyses showed a strong independent prognostic impact of high B7-H3 expression in all cancers and in the ERG negative subgroup. Comparison with previously analyzed frequent chromosomal deletions revealed a close association with Phosphatase and Tensin Homolog deletions. Analysis of B7-H3, alone or in combination with other markers, might be of clinical utility, especially in the subgroup of ERG negative prostate cancers.
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Affiliation(s)
- Sarah Bonk
- Department of General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Pinar Tasdelen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans Heinzer
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Graefen
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorsten Schlomm
- Department of Urology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören A Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Zheng F, Li P, Bachawal SV, Wang H, Li C, Yuan W, Huang B, Paulmurugan R. Assessment of Metastatic and Reactive Sentinel Lymph Nodes with B7-H3-Targeted Ultrasound Molecular Imaging: A Longitudinal Study in Mouse Models. Mol Imaging Biol 2020; 22:1003-1011. [PMID: 32034623 PMCID: PMC11162558 DOI: 10.1007/s11307-020-01478-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE To explore the potential of B7-H3-targeted ultrasound molecular imaging (USMI) for longitudinal assessment and differentiation of metastatic and reactive sentinel lymph nodes (SLNs) in mouse models. PROCEDURES Metastatic and reactive SLN models were established by injection of 4T1 breast cancer cells and complete Freund's adjuvant (CFA) respectively to the 4th mammary fat pad of female BALB/c mice. At day 21, 28, and 35 after inoculation, USMI was performed following intravenous injection of B7-H3-targeted microbubbles (MBB7-H3) or IgG-control microbubbles (MBcontrol). All SLNs were histopathologically examined after the last imaging session. RESULTS A total of 20 SLNs from tumor-bearing mice (T-SLNs) and five SLNs from CFA-injected mice (C-SLNs) were examined by USMI. Nine T-SLNs were histopathologically positive for metastasis (MT-SLNs). From day 21 to 35, T-SLNs showed a rising trend in MBB7-H3 signal with a steep increase in MT-SLNs at day 35 (213.5 ± 80.8 a.u.) as compared to day 28 (87.6 ± 77.2 a.u., P = 0.002) and day 21 (55.7 ± 35.5 a.u., P < 0.001). At day 35, MT-SLNs had significantly higher MBB7-H3 signal than non-metastatic T-SLNs (NMT-SLNs) (101.9 ± 48.0 a.u., P = 0.001) and C-SLNs (38.5 ± 34.0 a.u., P = 0.001); MBB7-H3 signal was significantly higher than MBcontrol in MT-SLNs (P = 0.001), but not in NMT-SLNs or C-SLNs (both P > 0.05). A significant correlation was detected between MBB7-H3 signal and volume fraction of metastasis in MT-SLNs (r = 0.76, P = 0.017). CONCLUSIONS B7-H3-targeted USMI allows differentiation of MT-SLNs from NMT-SLNs and C-SLNs in mouse models and has great potential to evaluate tumor burden in SLNs of breast cancer.
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Affiliation(s)
- Fengyang Zheng
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94305, USA
- Department of Ultrasound, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, People's Republic of China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, People's Republic of China
| | - Pan Li
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94305, USA
- Institute of Ultrasound Imaging of Chongqing Medical University, Chongqing, 400010, People's Republic of China
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People's Republic of China
| | - Sunitha V Bachawal
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94305, USA
| | - Huaijun Wang
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94305, USA
| | - Chaolun Li
- Department of Ultrasound, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, People's Republic of China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, People's Republic of China
| | - Wei Yuan
- Department of pathology, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, People's Republic of China
| | - Beijian Huang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, People's Republic of China.
- Shanghai Institute of Medical Imaging, Shanghai, 200032, People's Republic of China.
| | - Ramasamy Paulmurugan
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94305, USA.
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Xu Y, Xiao Y, Luo C, Liu Q, Wei A, Yang Y, Zhao L, Wang Y. Blocking PD-1/PD-L1 by an ADCC enhanced anti-B7-H3/PD-1 fusion protein engages immune activation and cytotoxicity. Int Immunopharmacol 2020; 84:106584. [PMID: 32422527 DOI: 10.1016/j.intimp.2020.106584] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/28/2020] [Accepted: 05/07/2020] [Indexed: 12/15/2022]
Abstract
Antibody therapy based on PD-1/PD-L1 blocking or ADCC effector has produced significant clinical benefit for cancer patients. We generated a novel anti-B7-H3 antibody (07B) and engineered the Fc fragment to enhance ADCC. To improve efficacy and tumor selectivity, we developed anti-B7-H3/PD-1 bispecific fusion proteins that simultaneously engaged tumor associate marker B7-H3 and immune suppressing ligand PD-L1 as well as enhanced ADCC to promote potent and highly selective tumor killing. Fusion proteins were designed by fusing human PD-1 extra domain to 07B in four different formats and showed good binding capacity to both targets. Indeed, the affinity of fusion proteins to B7-H3 is over 10,000 fold higher compared to that of the analogous PD-L1 and the blocking of fusion proteins to PD-L1 was worse but it greatly enhanced when bound to B7-H3, thus achieving directly PD-L1-blockade to B7-H3-expressing tumor cells. Importantly, IL-2 production was enhanced by fusion proteins from staphylococcal enterotoxin B (SEB) stimulated PBMC. Similarly, cytokines induced by fusion proteins was enhanced when co-cultured with stimulated CD8+ T cells and B7-H3/PD-L1 transfected raji cells. Additionally, fusion proteins improved activation to CD16a by Fc modification and delivered selective cytotoxicity to B7-H3 expressing tumor cells. In conclusion, fusion proteins blocked the PD-1/PD-L1 signal pathway and significantly increased potency of ADCC in a B7-H3-directed manner, thereby selectively activating CD8+ T cells and enhancing natural killing towards tumor. This novel fusion protein with its unique targeting preference may be useful to enhance efficacy and safety of immunotherapy for B7-H3-overexpressing malignancies.
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Affiliation(s)
- Yao Xu
- Sanhome-CPU Joint Laboratory, China Pharmaceutical University, Nanjing 211198, PR China; Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Yang Xiao
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Cheng Luo
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Qingxia Liu
- Sanhome-CPU Joint Laboratory, China Pharmaceutical University, Nanjing 211198, PR China; Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Aiqi Wei
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Yang Yang
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Liwen Zhao
- Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China
| | - Yong Wang
- Sanhome-CPU Joint Laboratory, China Pharmaceutical University, Nanjing 211198, PR China; Sanhome R&D Centre, Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 221116, PR China.
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Li F, Chen H, Wang D. Silencing of CD276 suppresses lung cancer progression by regulating integrin signaling. J Thorac Dis 2020; 12:2137-2145. [PMID: 32642118 PMCID: PMC7330387 DOI: 10.21037/jtd.2020.04.41] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Non-small cell lung cancer (NSCLC) is one of the cancers with the highest morbidity and mortality among the world. Studies have shown that the invasion and metastasis of tumor are biological characteristics of lung cancer, and also the main cause of treatment failure and patient death. In-depth study of lung cancer invasion related genes will help to explore the etiology of lung cancer, molecular typing and individualized treatment of lung cancer. Studies have shown that CD276 molecules are closely related to the prognosis of tumors, but the exact mechanism remains to be unclear. Methods We used the UALCAN and KM-plotter databases to investigate the expression of CD276 in human NSCLC and adjacent normal tissues, and its correlation with clinicopathology. In addition, we analyzed the function of CD276 in NSCLC cell by suppressing the expression of CD276 in A549 and H460 cells. Results In this study, we found that CD276 expression was significantly up-regulated in NSCLC tissues, and its expression was positively correlated with tumor stage in NSCLC. Silencing in CD276 inhibited cell invasion and migration by reducing integrin-associated protein expression. Conclusions Our results indicate functional role of CD276 in the progression of NSCLC.
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Affiliation(s)
- Fang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hengchi Chen
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Dali Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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