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Wilkerson AD, Juric I, Singh S, Rayman PA, Pavicic PG, Powers J, Parthasarathy PB, Al-Hilli Z, Ko JS, Chan T, Alban T, Montero AJ, Diaz-Montero CM. Responses to checkpoint inhibition in metastatic triple negative breast cancer driven by divergent myeloid phenotypes. COMMUNICATIONS MEDICINE 2025; 5:180. [PMID: 40382442 PMCID: PMC12085700 DOI: 10.1038/s43856-025-00860-4] [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: 09/20/2023] [Accepted: 04/10/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND Given the scarcity of effective therapeutic targets, metastatic triple negative breast cancer (mTNBC) has shorter survival times compared to other advanced breast cancer subtypes. Although chemo-immunotherapy with immune checkpoint inhibitors (ICIs) in PD-L1+ mTNBC has shown promise, survival benefit remains modest. Therefore, it is crucial to gain improved insight into the mechanisms underlying response and resistance to checkpoint inhibition in mTNBC. METHODS We employed single cell RNA sequencing (scRNAseq), single cell secretomics, and flow cytometry to identify transcriptomic and proteomic peripheral immune cell signatures associated with response and non-response to anti-PD-1/PD-L1 therapy and chemotherapy in mTNBC. RESULTS Transcriptomic analysis reveal divergent transcriptional programming of CD33+ myeloid cells between responders and non-responders, even in pretreatment PBMC samples. This divergence, in responders, is characterized by an immune-promoting CD33+ cell phenotype involving IL1b signaling compared to non-responders, where an immunosuppressive phenotype marked by IL1b inhibition is observed. These baseline differences become more pronounced during the course of chemo-immunotherapy. Differences in CD33+ cell phenotype result in functional differences in lymphocyte activities between responders and non-responders. Depletion of CD33+ cells in pre-treatment samples from non-responders, restores T cell effector function. CONCLUSION Our findings highlight CD33+ cell phenotype as a key determinant of response to chemo-immunotherapy, which can be assessed from peripheral blood. This offers a valuable tool in the context of metastatic TNBC, in which tissue sampling is often challenging.
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Affiliation(s)
- Avia D Wilkerson
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA
- Cleveland Clinic Foundation, Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland, OH, USA
| | - Ivan Juric
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA
| | - Salendra Singh
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA
| | - Patricia A Rayman
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA
| | - Paul G Pavicic
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA
| | - Jennifer Powers
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA
| | - Prerana Bangalore Parthasarathy
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA
| | - Zahraa Al-Hilli
- Cleveland Clinic Foundation, Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland, OH, USA
| | - Jennifer S Ko
- Cleveland Clinic Foundation, Pathology and Laboratory Medicine Institute, Cleveland, OH, USA
| | - Timothy Chan
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA
| | - Tyler Alban
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA.
| | - Alberto J Montero
- University Hospitals/Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
| | - C Marcela Diaz-Montero
- Cleveland Clinic Foundation, Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, USA.
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Peng G, Li B, Han H, Yuan Y, Mishra F, Huang Y, Liu ZR. Extracellular PKM2 modulates cancer immunity by regulating macrophage polarity. Cancer Immunol Immunother 2025; 74:195. [PMID: 40343475 PMCID: PMC12064527 DOI: 10.1007/s00262-025-04050-y] [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: 11/06/2024] [Accepted: 04/10/2025] [Indexed: 05/11/2025]
Abstract
Tumor controls its immunity by educating its microenvironment, including regulating polarity of tumor associated macrophages. It is well documented that cancer cells release PKM2 to facilitate tumor progression. We report here that the extracellular PKM2 (EcPKM2) modulates tumor immunity by facilitating M2 macrophage polarization in tumors. EcPKM2 interacts with integrin αvβ3 on macrophage to activate integrin-FAK-PI3K signal axis. Activation of FAK-PI3K by EcPKM2 suppresses PTEN expression, which subsequently upregulates arginase1 (Arg1) expression and activity in macrophage to facilitate M2 polarity. Our studies uncover a novel and important mechanism for modulation of tumor immunity. More importantly, an antibody against PKM2 that disrupts the interaction between EcPKM2 and integrin αvβ3 is effective in converting M2 macrophages to M1 macrophages in tumors, suggesting a new therapeutic strategy and target for cancer therapies. Combination of the anti-PKM2 antibody with checkpoint blockades provides enhanced treatment effects.
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Affiliation(s)
- Guangda Peng
- Department of Biology, Georgia State University, University Plaza, Atlanta, GA, 30303, USA
| | - Bin Li
- Department of Biology, Georgia State University, University Plaza, Atlanta, GA, 30303, USA
| | - Hongwei Han
- Department of Biology, Georgia State University, University Plaza, Atlanta, GA, 30303, USA
| | - Yi Yuan
- Department of Biology, Georgia State University, University Plaza, Atlanta, GA, 30303, USA
| | - Falguni Mishra
- Department of Biology, Georgia State University, University Plaza, Atlanta, GA, 30303, USA
| | - Yang Huang
- Department of Biology, Georgia State University, University Plaza, Atlanta, GA, 30303, USA
| | - Zhi-Ren Liu
- Department of Biology, Georgia State University, University Plaza, Atlanta, GA, 30303, USA.
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3
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Hu H, Zhang M. PD-1 involvement in CD8+ tumor-infiltrating lymphocytes in patients with colonic-derived peritoneal adenocarcinoma. Braz J Med Biol Res 2025; 58:e14467. [PMID: 40243819 PMCID: PMC11996165 DOI: 10.1590/1414-431x2025e14467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 03/03/2025] [Indexed: 04/18/2025] Open
Abstract
Immune checkpoint blockade with anti-programmed cell death protein 1 (PD-1) antibody has become a hot topic for the treatment of human malignancies. Here, we aimed to investigate whether the percentage of PD-1 in CD8+ tumor-infiltrating lymphocytes correlates with the progression of colonic-derived peritoneal adenocarcinoma (PA). Peripheral blood and tissue samples from 40 patients with colonic-derived PA were collected and subjected to multicolor flow cytometry analysis of the percentage of peripheral PD-1+CD8+ T cells. The multiple immunofluorescence method was used to detect the positive percentages of PD-1 and CD8 in the tissues. The enrolled patients were divided into groups by recurrence interval (less than 6 months, greater than two years) and differentiation grade (low, well/moderate). In the colonic-derived PA tissues, the percentages of cells positive for PD-1, CD8, and PD-1+CD8+ were higher in the paracancer tissues compared with cancerous tissues. PD-1+CD8+ T cells had an increased presence in peripheral blood than in tissues. Our data also indicated that colonic-derived PA patients with less than a six-month recurrence interval presented higher levels of PD-1 in CD8+ tumor-infiltrating lymphocytes in than the two-year recurrence group. The level of PD-1+CD8+T cells in the tissue correlated with the clinical outcome of colonic-derived PA. Higher percentages of PD-1+CD8+T cells correlated with a shorter progression-free survival (PFS). PD-1 in CD8+ tumor-infiltrating lymphocytes may have a good predictive value for immunotherapy of colonic-derived PA and act as the prognostic factor for PFS.
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Affiliation(s)
- Huihui Hu
- Department of Clinical Laboratory, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Man Zhang
- Department of Clinical Laboratory, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
- Clinical Laboratory Medicine, Peking University Ninth School of Clinical Medicine, Beijing, China
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Li M, Zheng A, Song M, Jin F, Pang M, Zhang Y, Wu Y, Li X, Zhao M, Li Z. From text to insight: A natural language processing-based analysis of burst and research trends in HER2-low breast cancer patients. Ageing Res Rev 2025; 106:102692. [PMID: 39993452 DOI: 10.1016/j.arr.2025.102692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 01/01/2025] [Accepted: 02/10/2025] [Indexed: 02/26/2025]
Abstract
With the intensification of population aging, the proportion of elderly breast cancer patients is continuously increasing, among which those with low HER2 expression account for approximately 45 %-55 % of all cases within traditional HER2-negative breast cancer. Concurrently, the significant therapeutic effect of T-DXd on patients with HER2-low tumors has brought this group into the public spotlight. Since the clinical approval of T-DXd in 2019, there has been a significant vertical surge in the volume of publications within this domain. We analyzed 512 articles on HER2-low breast cancer from the Web of Science Core Collection using bibliometrics, topic modeling, and knowledge graph techniques to summarize the current state and trends of research in this domain. Research efforts are particularly concentrated in the United States and China. Our analysis revealed six main research directions: HER2 detection, omics and clinical biomarkers, basic and translational research, neoadjuvant therapy and prognosis, progress of ADC drugs and clinical trials. To enhance the therapeutic efficacy and safety of antibodydrug conjugates (ADCs), researchers are actively exploring potential drug candidates other than T-DXd, with numerous ADC drugs emerging in clinical practice and trials. By incorporating emerging treatment strategies such as immunotherapy and employing circulating tumor cell (CTC) detection techniques, progress has been made toward improving the prognosis of patients with low HER2 expression. We believe that these research efforts hold promise as compelling evidence that HER2-low breast cancer may constitute a distinct and independent subtype.
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Affiliation(s)
- Muyao Li
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Ang Zheng
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Mingjie Song
- Department of General Medicine, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Feng Jin
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Mengyang Pang
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Yuchong Zhang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Ying Wu
- Department of General Medicine, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China; Phase I Clinical Trails Center, The First Hospital of China Medical University, Shenyang, Liaoning 110101, China.
| | - Xin Li
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Mingfang Zhao
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Zhi Li
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China; National Clinical Research Center for Laboratory Medicine, Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China; Research Unit of Medical Laboratory, Chinese Academy of Medical Sciences, China.
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5
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Fan J, Qin Y, Qiu W, Liang J, Xiao C, Xie Q, Tong C, Yuan L, Long Y, Liu B. Gamabufotalin loaded micro-nanocomposites for multimodal therapy of metastatic TNBC by efficiently inducing ICD. Biomaterials 2025; 314:122851. [PMID: 39366186 DOI: 10.1016/j.biomaterials.2024.122851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/30/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024]
Abstract
Gamabufotalin (CS-6), a main active compound derived from Chinese medicine Chansu, exhibits a robust inhibitory effect on programmed death-ligand 1 (PD-L1) in triple-negative breast cancer (TNBC) cells. Despite its potential for tumor therapy, the medical application of CS-6 is constrained by its hydrophobic nature, lack of targeting capability, and weak immunogenic cell death (ICD) effect. To address these limitations and improve the therapeutic efficiency of this drug against metastatic TNBC, we designed a new kind of CS-6@CPB-S.lux that integrates carboxy-Prussian blue nanoparticles (CPB NPs), CS-6, and attenuated Salmonella typhimurium (S.lux) for TNBC therapy. In vitro and in vivo results have confirmed that CS-6@CPB NPs were efficiently delivered to neoplastic tissue by the tumor hypoxic chemotaxis property of S.lux, wherein the nanomedicine induced significant tumor cell necroptosis and apoptosis via photothermal therapy (PTT) of CPB NPs and chemotherapy of CS-6, which elicited ICD and inhibited PD-L1 expression, resulting in dendritic cells (DCs) maturation and effector T cells activation to comprehensively eliminate tumors. Additionally, the CS-6@CPB-S.lux + Laser treatment significantly transformed the immunosuppressive tumor microenvironment (TME), enhancing antitumor immunity through promoting the polarization of tumor-associated macrophages into antitumorigenic M1 and reducing Tregs recruitment. Consequently, this comprehensive therapy not only inhibited primary and abscopal tumor progression but also prevented TNBC metastasis, which significantly prolonged survival time in animal models. In summary, these findings indicated an alternative approach for metastatic TNBC therapy.
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Affiliation(s)
- Jialong Fan
- College of Biology, School of Biomedical Sciences, Hunan University, Changsha, 410082, China
| | - Yan Qin
- College of Biology, School of Biomedical Sciences, Hunan University, Changsha, 410082, China; TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Wensheng Qiu
- College of Biology, School of Biomedical Sciences, Hunan University, Changsha, 410082, China
| | - Jiahao Liang
- College of Biology, School of Biomedical Sciences, Hunan University, Changsha, 410082, China
| | - Chang Xiao
- College of Biology, School of Biomedical Sciences, Hunan University, Changsha, 410082, China
| | - Qian Xie
- Department of Pharmacy, Maternal and Child Health of Hunan Province, Changsha, 410008, China
| | - Chunyi Tong
- College of Biology, School of Biomedical Sciences, Hunan University, Changsha, 410082, China
| | - Liqin Yuan
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
| | - Ying Long
- College of Biology, School of Biomedical Sciences, Hunan University, Changsha, 410082, China.
| | - Bin Liu
- College of Biology, School of Biomedical Sciences, Hunan University, Changsha, 410082, China; NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, 750004, China.
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6
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Heldager Pedersen N, Nascimento Melsted W, Scheike T, Eriksen JO, Reznitsky FM, Bzorek M, Lænkholm AV, Hviid TVF. Effect modification between HLA-F and CD56 markers reveals differences in survival for triple-negative breast cancer patients. Hum Immunol 2024; 85:111152. [PMID: 39405828 DOI: 10.1016/j.humimm.2024.111152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 10/01/2024] [Accepted: 10/01/2024] [Indexed: 12/14/2024]
Abstract
Triple-negative breast cancer (TNBC) is usually aggressive and challenging to treat. With high tumour immunogenicity TNBC patients might benefit from immunotherapy. We evaluated heterogeneous immune profiles of individual tumours in relation to clinical development to identify immune markers and their mutual expression. We assessed 122 biopsies from patients with primary TNBC tumours by automated image analysis of immunohistochemically stained tissue microarrays. Tumour-infiltrating lymphocytes (TILs), expression of HLA I molecules (HLA-ABC, HLA-G, HLA-E, HLA-F) and their mutual associations, as well as associations with other immune response markers (PD-L1, FOXP3, CD4, CD8, CD56) were investigated together with survival outcomes. Analysis of effect modification between HLA-F and CD56 showed longer disease-free survival and time-to-recurrence for tumours with low expression of both markers. TILs were significantly associated with tumour grade and with HLA-F, PD-L1, FOXP3 and CD8 expression, and were significantly associated with longer disease-free survival, also in multivariate analysis. Expression of all immune markers was positively correlated with each other, except CD56. The study highlights the complex immune regulation in TNBC stressing the importance of evaluating the immune landscape of individual tumours to identify patients that can benefit from immunotherapy. The finding of an effect modulation between HLA-F and CD56 is one aspect.
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Affiliation(s)
- Nanna Heldager Pedersen
- Centre for Immune Regulation and Reproductive Immunology (CIRRI), Department of Clinical Biochemistry, Zealand University Hospital, Roskilde, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Wenna Nascimento Melsted
- Centre for Immune Regulation and Reproductive Immunology (CIRRI), Department of Clinical Biochemistry, Zealand University Hospital, Roskilde, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Scheike
- Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | - Jens Ole Eriksen
- Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark
| | - Frances M Reznitsky
- Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark
| | - Michael Bzorek
- Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark
| | - Anne-Vibeke Lænkholm
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark
| | - Thomas Vauvert F Hviid
- Centre for Immune Regulation and Reproductive Immunology (CIRRI), Department of Clinical Biochemistry, Zealand University Hospital, Roskilde, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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7
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Wofford W, Kim J, Kim D, Janneh AH, Lee HG, Atilgan FC, Oleinik N, Kassir MF, Saatci O, Chakraborty P, Tokat UM, Gencer S, Howley B, Howe P, Mehrotra S, Sahin O, Ogretmen B. Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response. Cell Rep 2024; 43:114532. [PMID: 39046874 PMCID: PMC11404065 DOI: 10.1016/j.celrep.2024.114532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 05/17/2024] [Accepted: 07/09/2024] [Indexed: 07/27/2024] Open
Abstract
Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ regulatory T cells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
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Affiliation(s)
- Wyatt Wofford
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Jisun Kim
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Dosung Kim
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Alhaji H Janneh
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Han Gyul Lee
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - F Cansu Atilgan
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Natalia Oleinik
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Mohamed Faisal Kassir
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Ozge Saatci
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Paramita Chakraborty
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Surgery, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Unal Metin Tokat
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Salih Gencer
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Istanbul Medipol University, Health Science and Technologies Research Institute (SABİTA), Cancer Research Center, Istanbul, Turkey
| | - Breege Howley
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Philip Howe
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Shikhar Mehrotra
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Surgery, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Ozgur Sahin
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
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Kang S, Gil YG, Chae SY, Jang H, Min DH. Pt-Te-Nanorod-Based Photothermal Chemokine Immunotherapy for All Stages of Cancer via Adaptive and Innate Immunity. ACS APPLIED MATERIALS & INTERFACES 2024; 16:37555-37568. [PMID: 39007297 DOI: 10.1021/acsami.4c06048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
The chemokine (C-X-C) motif ligand 9 (CXCL9) is one of the lymphocyte-traffic-involved chemokines. Despite the immunotherapeutic potential of CXCL9 for recruiting effector T cells (cluster of differentiation 4+ (CD4+) and CD8+ T cells) and natural killer cells (NK cells) around the tumors, practical applications of CXCL9 have been limited because of its immune toxicity and lack of stability in vivo. To overcome these limitations, we designed and synthesized Pt-Te nanorods (PtTeNRs), which exhibited excellent photothermal conversion efficiency with stable CXCL9 payload characteristics under the physiological conditions of in vivo environments. We developed a CXCL9-based immunotherapy strategy by utilizing the unique physicochemical properties of developed PtTeNRs. The investigation revealed that the PtTeNR-loaded CXCL9 was effectively accumulated in the tumor, subsequently released in a sustained manner, and successfully recruited effector T cells for immunotherapy of the designated tumor tissue. In addition, a synergistic effect was observed between the photothermal (PT) therapy and antiprogrammed cell death protein 1 (aPD-1) antibody. In this study, we demonstrated that PtTeNR-based CXCL9, PT, and aPD-1 antibody trimodal therapy delivers an outstanding tumor suppression effect in all stages of cancer, including phases 1-4 and tumor recurrence.
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Affiliation(s)
- Seounghun Kang
- Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea
| | - Yeong-Gyu Gil
- Department of Chemistry, Kwangwoon University, 20 Gwangwoon-ro, Nowon-gu, Seoul 01897, Republic of Korea
| | - Se-Youl Chae
- Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea
| | - Hongje Jang
- Department of Chemistry, Kwangwoon University, 20 Gwangwoon-ro, Nowon-gu, Seoul 01897, Republic of Korea
| | - Dal-Hee Min
- Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea
- Institute of Biotherapeutics Convergence Technology, Lemonex Inc., Seoul 06683, Republic of Korea
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9
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Subbarayan R, Srinivasan D, Balakrishnan R, Kumar A, Usmani SS, Srivastava N. DNA damage response and neoantigens: A favorable target for triple-negative breast cancer immunotherapy and vaccine development. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 389:104-152. [PMID: 39396845 DOI: 10.1016/bs.ircmb.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature and limited therapeutic options. The interplay between DNA damage response (DDR) mechanisms and the emergence of neoantigens represents a promising avenue for developing targeted immunotherapeutic strategies and vaccines for TNBC. The DDR is a complex network of cellular mechanisms designed to maintain genomic integrity. In TNBC, where genetic instability is a hallmark, dysregulation of DDR components plays a pivotal role in tumorigenesis and progression. This review explores the intricate relationship between DDR and neoantigens, shedding light on the potential vulnerabilities of TNBC cells. Neoantigens, arising from somatic mutations in cancer cells, represent unique antigens that can be recognized by the immune system. TNBC's propensity for genomic instability leads to an increased mutational burden, consequently yielding a rich repertoire of neoantigens. The convergence of DDR and neoantigens in TNBC offers a distinctive opportunity for immunotherapeutic targeting. Immunotherapy has revolutionized cancer treatment by harnessing the immune system to selectively target cancer cells. The unique immunogenicity conferred by DDR-related neoantigens in TNBC positions them as ideal targets for immunotherapeutic interventions. This review also explores various immunotherapeutic modalities, including immune checkpoint inhibitors (ICIs), adoptive cell therapies, and cancer vaccines, that leverage the DDR and neoantigen interplay to enhance anti-tumor immune responses. Moreover, the potential for developing vaccines targeting DDR-related neoantigens opens new frontiers in preventive and therapeutic strategies for TNBC. The rational design of vaccines tailored to the individual mutational landscape of TNBC holds promise for precision medicine approaches. In conclusion, the convergence of DDR and neoantigens in TNBC presents a compelling rationale for the development of innovative immunotherapies and vaccines. Understanding and targeting these interconnected processes may pave the way for personalized and effective interventions, offering new hope for patients grappling with the challenges posed by TNBCs.
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Affiliation(s)
- Rajasekaran Subbarayan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, FAHS, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Dhasarathdev Srinivasan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, FAHS, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Ranjith Balakrishnan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, FAHS, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Ajeet Kumar
- Department of Psychiatry, Washington university School of Medicine, St louis, MO, United States
| | - Salman Sadullah Usmani
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States.
| | - Nityanand Srivastava
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, United States.
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10
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Roussos Torres ET, Ho WJ, Danilova L, Tandurella JA, Leatherman J, Rafie C, Wang C, Brufsky A, LoRusso P, Chung V, Yuan Y, Downs M, O'Connor A, Shin SM, Hernandez A, Engle EL, Piekarz R, Streicher H, Talebi Z, Rudek MA, Zhu Q, Anders RA, Cimino-Mathews A, Fertig EJ, Jaffee EM, Stearns V, Connolly RM. Entinostat, nivolumab and ipilimumab for women with advanced HER2-negative breast cancer: a phase Ib trial. NATURE CANCER 2024; 5:866-879. [PMID: 38355777 PMCID: PMC11552660 DOI: 10.1038/s43018-024-00729-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 01/17/2024] [Indexed: 02/16/2024]
Abstract
We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 ( NCT02453620 ). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.
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Affiliation(s)
- Evanthia T Roussos Torres
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
- Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Won J Ho
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Ludmila Danilova
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Joseph A Tandurella
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - James Leatherman
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Christine Rafie
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
- University of Miami Miller School of Medicine, Miami, FL, USA
| | - Chenguang Wang
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Adam Brufsky
- University of Pittsburgh Cancer Institute and UPMC Cancer Center, Pittsburgh, PA, USA
| | | | | | - Yuan Yuan
- Cedars-Sinai Cancer, Los Angeles, CA, USA
| | - Melinda Downs
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Ashley O'Connor
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Sarah M Shin
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Alexei Hernandez
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Elizabeth L Engle
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Richard Piekarz
- Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, Bethesda, MD, USA
| | - Howard Streicher
- Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, Bethesda, MD, USA
| | - Zahra Talebi
- Division of Pharmaceutics and Pharmacology, The Ohio State University, Columbus, OH, USA
| | - Michelle A Rudek
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Qingfeng Zhu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Robert A Anders
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Ashley Cimino-Mathews
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Elana J Fertig
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Elizabeth M Jaffee
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Vered Stearns
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Roisin M Connolly
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
- Cancer Research @UCC, College of Medicine and Health, University College Cork, Cork, Ireland.
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11
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Santos DL, São Marcos BDF, de Sousa GF, Cruz LCDO, Barros BRDS, Nogueira MCDBL, Oliveira THDA, Silva AJD, Santos VEP, de Melo CML, de Freitas AC. Immunological Response against Breast Lineage Cells Transfected with Human Papillomavirus (HPV). Viruses 2024; 16:717. [PMID: 38793599 PMCID: PMC11125976 DOI: 10.3390/v16050717] [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: 03/18/2024] [Revised: 04/15/2024] [Accepted: 04/29/2024] [Indexed: 05/26/2024] Open
Abstract
Breast cancer is the most common neoplasm worldwide. Viral infections are involved with carcinogenesis, especially those caused by oncogenic Human Papillomavirus (HPV) genotypes. Despite the detection of HPV in breast carcinomas, the virus's activity against this type of cancer remains controversial. HPV infection promotes remodeling of the host's immune response, resulting in an immunosuppressive profile. This study assessed the individual role of HPV oncogenes in the cell line MDA-MB-231 transfected with the E5, E6, and E7 oncogenes and co-cultured with peripheral blood mononuclear cells. Immunophenotyping was conducted to evaluate immune system modulation. There was an increase in CD4+ T cell numbers when compared with non-transfected and transfected MDA-MB-231, especially in the Treg profile. Pro-inflammatory intracellular cytokines, such as IFN-γ, TNF-α, and IL-17, were impaired by transfected cells, and a decrease in the cytolytic activity of the CD8+ and CD56+ lymphocytes was observed in the presence of HPV oncogenes, mainly with E6 and E7. The E6 and E7 oncogenes decrease monocyte expression, activating the expected M1 profile. In the monocytes found, a pro-inflammatory role was observed according to the cytokines released in the supernatant. In conclusion, the MDA-MB-231 cell lineage transfected with HPV oncogenes can downregulate the number and function of lymphocytes and monocytes.
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Affiliation(s)
- Daffany Luana Santos
- Laboratory of Molecular Studies and Experimental Therapy, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (D.L.S.); (B.d.F.S.M.); (A.J.D.S.); (V.E.P.S.)
| | - Bianca de França São Marcos
- Laboratory of Molecular Studies and Experimental Therapy, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (D.L.S.); (B.d.F.S.M.); (A.J.D.S.); (V.E.P.S.)
| | - Georon Ferreira de Sousa
- Keizo Asami Immunopathology Laboratory, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (G.F.d.S.); (L.C.d.O.C.); (B.R.d.S.B.); (M.C.d.B.L.N.); (C.M.L.d.M.)
- Department of Antibiotics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil
| | - Leonardo Carvalho de Oliveira Cruz
- Keizo Asami Immunopathology Laboratory, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (G.F.d.S.); (L.C.d.O.C.); (B.R.d.S.B.); (M.C.d.B.L.N.); (C.M.L.d.M.)
- Department of Antibiotics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil
| | - Bárbara Rafaela da Silva Barros
- Keizo Asami Immunopathology Laboratory, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (G.F.d.S.); (L.C.d.O.C.); (B.R.d.S.B.); (M.C.d.B.L.N.); (C.M.L.d.M.)
- Department of Antibiotics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil
| | - Mariane Cajuba de Britto Lira Nogueira
- Keizo Asami Immunopathology Laboratory, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (G.F.d.S.); (L.C.d.O.C.); (B.R.d.S.B.); (M.C.d.B.L.N.); (C.M.L.d.M.)
- Vitória Academic Center, Federal University of Pernambuco, Rua do Alto do Reservatório s/n, Bela Vista, Vitória de Santo Antão 55608-680, Pernambuco, Brazil
| | | | - Anna Jessica Duarte Silva
- Laboratory of Molecular Studies and Experimental Therapy, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (D.L.S.); (B.d.F.S.M.); (A.J.D.S.); (V.E.P.S.)
| | - Vanessa Emanuelle Pereira Santos
- Laboratory of Molecular Studies and Experimental Therapy, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (D.L.S.); (B.d.F.S.M.); (A.J.D.S.); (V.E.P.S.)
| | - Cristiane Moutinho Lagos de Melo
- Keizo Asami Immunopathology Laboratory, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (G.F.d.S.); (L.C.d.O.C.); (B.R.d.S.B.); (M.C.d.B.L.N.); (C.M.L.d.M.)
- Department of Antibiotics, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil
| | - Antonio Carlos de Freitas
- Laboratory of Molecular Studies and Experimental Therapy, Department of Genetics, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235. Cidade Universitária, Recife 50670-901, Pernambuco, Brazil; (D.L.S.); (B.d.F.S.M.); (A.J.D.S.); (V.E.P.S.)
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12
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Hu H, Zhang M. Correlation analysis between peripheral blood dendritic cell subsets and PD-1 in patients with peritoneal adenocarcinoma. Braz J Med Biol Res 2024; 57:e13192. [PMID: 38381884 PMCID: PMC10880883 DOI: 10.1590/1414-431x2023e13192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 12/27/2023] [Indexed: 02/23/2024] Open
Abstract
The aim of this study was to explore the association between differential percentages of dendritic cell (DC) subsets in peripheral blood and malignancy (grade and lymph node metastasis) of peritoneal adenocarcinoma patients and the frequencies of dendritic cell subsets in the normal controls. The peripheral blood of 30 patients with peritoneal adenocarcinoma and 12 healthy controls were collected for multicolor flow cytometry analysis. Peritoneal adenocarcinoma patients were grouped according to the malignant degree (grade and lymph node metastasis). Percentages of myeloid DCs (mDCs) and its subsets MDC1 and MDC2 in DCs were lower in peripheral blood of patients with peritoneal adenocarcinoma than in normal controls. The percentages of plasmacytoid dendritic cells (pDCs) and CD16+mDCs in DCs were higher than in normal controls. Compared with poor differentiation grade, patients with well/moderate differentiation grade had an increased percentage of CD16+mDCs. Contrary to CD16+mDCs, the percentage of MDC1 was lower in the well/moderate differentiation grade group. In patients with no lymph node metastasis, pDCs and CD16+mDCs levels were higher compared with patients with lymph node metastasis. mDCs and MDC1 levels had opposite results. pDCs were positively correlated with CD16+mDCs in peripheral blood of peritoneal patients, as was mDCs and MDC1. CD16+mDCs were negatively correlated with MDC1. The percentages of pDCs and CD16+mDCs in DCs were positively correlated with CD3+CD8+T cells, and pDCs also positively correlated with CD8+PD-1+T cells. Our results revealed that DCs subsets correlated with peritoneal adenocarcinoma malignancy. Dendritic cells play an independent role in the immune function of peritoneal adenocarcinoma.
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Affiliation(s)
- Huihui Hu
- Department of Clinical Laboratory, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Man Zhang
- Department of Clinical Laboratory, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
- Clinical Laboratory Medicine, Peking University Ninth School of Clinical Medicine, Beijing, China
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13
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Khan MJ, Singh AK, Sultana R, Singh PP, Khan A, Saxena S. Breast cancer: A comparative review for breast cancer detection using machine learning techniques. Cell Biochem Funct 2023; 41:996-1007. [PMID: 37812062 DOI: 10.1002/cbf.3868] [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: 06/10/2023] [Revised: 09/05/2023] [Accepted: 09/24/2023] [Indexed: 10/10/2023]
Abstract
Breast cancer is the most common cancer among women globally and presents a significant challenge due to its rising incidence and fatality rates. Factors such as cultural, socioeconomic, and educational barriers contribute to inadequate awareness and access to healthcare services, often leading to delayed diagnoses and poor patient outcomes. Furthermore, fostering a collaborative approach among healthcare providers, policymakers, and community leaders is crucial in addressing this critical women's health issue, reducing mortality rates, alleviating, and the overall burden of breast cancer. The main goal of this review is to explore various techniques of machine learning algorithms to examine high accuracy and early detection of breast cancer for the safe health of women.
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Affiliation(s)
- Mohd Jawed Khan
- Department of Computer Science & Engineering, Central Institute of Technology, Kokrajhar, Assam, India
| | - Arun Kumar Singh
- Department of Computer Science and Engineering, Greater Noida Institute of Technology, Greater Noida, India
| | - Razia Sultana
- Department of Biotechnology, School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | - Pankaj Pratap Singh
- Department of Computer Science & Engineering, Central Institute of Technology, Kokrajhar, Assam, India
| | - Asif Khan
- Department of Computer Science and Engineering, Greater Noida Institute of Technology, Greater Noida, India
| | - Sandeep Saxena
- Department of Computer Science and Engineering, Greater Noida Institute of Technology, Greater Noida, India
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14
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Sadr S, Borji H. Echinococcus granulosus as a Promising Therapeutic Agent against Triplenegative Breast Cancer. CURRENT CANCER THERAPY REVIEWS 2023; 19:292-297. [DOI: 10.2174/1573394719666230427094247] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 11/06/2022] [Accepted: 01/19/2023] [Indexed: 08/19/2024]
Abstract
Abstract:Breast cancer is a major cause of cancer deaths in women, with approximately 1.2 million new cases per year. Current treatment options for breast cancer include surgery, radiation, hormone therapy, and chemotherapy. However, the non-selective cytotoxicity of chemotherapeutic agents often leads to severe side effects, while drug resistance can worsen patient outcomes. Therefore, the development of more effective and less toxic anticancer drugs is a critical need. This study aimed to review the literature on Echinococcus granulosus antigens with anticancer potential against triple-negative breast cancer. Recent studies have suggested that certain parasite antigens may have potential anticancer effects. Specifically, research has shown that echinococcosis, a disease caused by the parasitic cestode Echinococcus granulosus, may have a protective effect against cancer. These findings offer new insights into the potential use of E. granulosus antigens in the development of novel cancer therapies and tumor cell vaccines. The findings of recent studies suggested that E. granulosus antigens may have the potential to be used in effective and less toxic cancer treatments. However, further research is needed to fully understand the mechanisms behind the anticancer effects of these antigens and develop new cancer therapies and vaccines
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Affiliation(s)
- Soheil Sadr
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hassan Borji
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
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15
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Varghese GR, Patra D, Jaikumar VS, Rajan A, Latha NR, Srinivas P. βhCG mediates immune suppression through upregulation of CD11b + Gr1 + myeloid derived suppressor cells, CD206 + M2 macrophages, and CD4 + FOXP3 + regulatory T-cells in BRCA1 deficient breast cancers. Immunology 2023; 170:270-285. [PMID: 37340549 DOI: 10.1111/imm.13673] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 05/17/2023] [Indexed: 06/22/2023] Open
Abstract
BRCA1 mutation is reported in about 70% of all triple negative breast cancers (TNBC), while BRCA1 defect due to promoter hypermethylation is seen in about 30%-60% of sporadic breast cancers. Although PARP inhibitors and platinum-based chemotherapy are used to treat these cancers, more efficient therapeutic approaches are required to overcome the resistance to treatment. Our previous findings have reported elevated βhCG expression but not αhCG in BRCA1 deficient breast cancers. As βhCG causes immune suppression in pregnancy, this study explored the immunomodulatory effect of βhCG in BRCA1mutated/deficient TNBC. We observed that Th1, Th2, and Th17 cytokines are upregulated in the presence of βhCG in BRCA1 defective cancers. In NOD-SCID and syngeneic mouse models, βhCG increases the frequency of Myeloid-derived suppressor cells in tumour tissues and contributes to macrophage reprogramming from antitumor M1 to pro-tumour M2 phenotype. βhCG reduces the CD4+ T-cell infiltration while increasing the density of CD4+ CD25+ FOXP3+ regulatory T-cell in BRCA1 deficient tumour tissues. In contrast, xenograft tumours with βhCG knocked down TNBC cells did not show these immune suppressive effects. We have also shown that βhCG upregulates pro-tumorigenic markers arginase1(Arg1), inducible nitric oxide synthase, PD-L1/PD-1, and NFκB in BRCA1 defective tumours. Thus, for the first time, this study proves that βhCG suppresses the host antitumor immune response and contributes to tumour progression in BRCA1 deficient tumours. This study will help develop new immunotherapeutic approaches for treating BRCA1 defective TNBC by regulating βhCG.
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Affiliation(s)
- Geetu Rose Varghese
- Cancer Research Program 6, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
- Research Centre, University of Kerala, Thiruvananthapuram, Kerala, India
| | - Dipyaman Patra
- Cancer Research Program 6, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Vishnu Sunil Jaikumar
- Cancer Research Program 6, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
- Animal Research Facility, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Arathi Rajan
- Cancer Research Program 6, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Neetha R Latha
- Cancer Research Program 6, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Priya Srinivas
- Cancer Research Program 6, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
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16
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Das PK, Siddika A, Rashel KM, Auwal A, Soha K, Rahman MA, Pillai S, Islam F. Roles of long noncoding RNA in triple-negative breast cancer. Cancer Med 2023; 12:20365-20379. [PMID: 37795578 PMCID: PMC10652353 DOI: 10.1002/cam4.6600] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/02/2023] [Accepted: 09/17/2023] [Indexed: 10/06/2023] Open
Abstract
INTRODUCTION Long noncoding RNAs (lncRNAs) play crucial roles in regulating various hallmarks in cancers. Triple-negative (Estrogen receptor, ER; Human epidermal growth factor receptor 2, HER2; Progesterone receptor, PR) breast cancer (TNBC) is the most aggressive form of breast cancers with a poor prognosis and no available molecular targeted therapy. METHODS We reviewed the current literature on the roles of lncRNAs in the pathogenesis, therapy resistance, and prognosis of patients with TBNC. RESULTS LncRNAs are associated with TNBC pathogenesis, therapy resistance, and prognosis. For example, lncRNAs such as small nucleolar RNA host gene 12 (SNHG12), highly upregulated in liver cancer (HULC) HOX transcript antisense intergenic RNA (HOTAIR), lincRNA-regulator of reprogramming (LincRNA-ROR), etc., are aberrantly expressed in TNBC and are involved in the pathogenesis of the disease. LncRNAs act as a decoy, scaffold, or sponge to regulate the expression of genes, miRNAs, and transcription factors associated with pathogenesis and progression of TNBC. Moreover, lncRNAs such as ferritin heavy chain 1 pseudogene 3 (FTH1P3), BMP/OP-responsive gene (BORG) contributes to the therapy resistance property of TNBC through activating ABCB1 (ATP-binding cassette subfamily B member 1) drug efflux pumps by increasing DNA repair capacity or by inducing signaling pathway involved in therapeutic resistance. CONCLUSION In this review, we outline the functions of various lncRNAs along with their molecular mechanisms involved in the pathogenesis, therapeutic resistance of TBNC. Also, the prognostic implications of lncRNAs in patients with TNBC is illustrated. Moreover, potential strategies targeting lncRNAs against highly aggressive TNBC is discussed in this review.
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Affiliation(s)
- Plabon Kumar Das
- Department of Biochemistry & Molecular BiologyRajshahi UniversityRajshahiBangladesh
- Institute for GlycomicsGriffith UniversityGold CoastAustralia
| | - Ayesha Siddika
- Institute of Tissue Banking & Biomaterial Research, Atomic Energy Research Establishment (AERE) SavarDhakaBangladesh
| | - Khan Mohammad Rashel
- Department of Biochemistry & Molecular BiologyRajshahi UniversityRajshahiBangladesh
| | - Abdul Auwal
- Department of Biochemistry & Molecular BiologyRajshahi UniversityRajshahiBangladesh
| | - Kazi Soha
- Department of Biochemistry & Molecular BiologyRajshahi UniversityRajshahiBangladesh
| | - Md. Arifur Rahman
- Department of Biochemistry & Molecular BiologyRajshahi UniversityRajshahiBangladesh
| | - Suja Pillai
- School of Biomedical SciencesUniversity of QueenslandSaint LuciaAustralia
| | - Farhadul Islam
- Department of Biochemistry & Molecular BiologyRajshahi UniversityRajshahiBangladesh
- Institute for GlycomicsGriffith UniversityGold CoastAustralia
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17
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Selem NA, Nafae H, Manie T, Youness RA, Gad MZ. Let-7a/cMyc/CCAT1/miR-17-5p Circuit Re-sensitizes Atezolizumab Resistance in Triple Negative Breast Cancer through Modulating PD-L1. Pathol Res Pract 2023; 248:154579. [PMID: 37301086 DOI: 10.1016/j.prp.2023.154579] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 05/23/2023] [Accepted: 05/27/2023] [Indexed: 06/12/2023]
Abstract
BACKGROUND Triple negative breast cancer (TNBC) is an immunogenically hot tumor. The immune checkpoint blockades (ICBs) have been recently emerged as promising therapeutic candidates for several malignancies including TNBC. Yet, the development of innate and/or adaptive resistance by TNBC patients towards ICBs such as programmed death-ligand 1 (PD-L1) inhibitors (e.g. Atezolizumab) shed the light on importance of identifying the underlying mechanisms regulating PD-L1 in TNBC. Recently, it was reported that non-coding RNAs (ncRNAs) perform a fundamental role in regulating PD-L1 expression in TNBC. Hence, this study aims to explore a novel ncRNA axis tuning PD-L1 in TNBC patients and investigate its possible involvement in fighting Atezolizumab resistance. METHODS In-silico screening was executed to identify ncRNAs that could potentially target PD-L1. Screening of PD-L1 and the nominated ncRNAs (miR-17-5p, let-7a and CCAT1 lncRNA) was performed in BC patients and cell lines. Ectopic expression and/or knockdown of respective ncRNAs were performed in MDA-MB-231. Cellular viability, migration and clonogenic capacities were evaluated using MTT, scratch assay and colony-forming assay, respectively. RESULTS PD-L1 was upregulated in BC patients, especially in TNBC patients. PD-L1 is positively associated with lymph node metastasis and high Ki-67 in recruited BC patients. Let-7a and miR-17-5p were nominated as potential regulators of PD-L1. Ectopic expression of let-7a and miR-17-5p caused a noticeable reduction in PD-L1 levels in TNBC cells. In order to investigate the whole ceRNA circuit regulating PD-L1 in TNBC, intensive bioinformatic studies were performed. The lncRNA, Colon Cancer-associated transcript 1 (CCAT1), was reported to target PD-L1 regulating miRNAs. Results showed that CCAT1 is an upregulated oncogenic lncRNA in TNBC patients and cell lines. CCAT1 siRNAs induced a noticeable reduction in PD-L1 levels and a marked increase in miR-17-5p level, building up a novel regulatory axis CCAT1/miR-17-5p/PD-L1 in TNBC cells that was tuned by the let-7a/c-Myc engine. On the functional level, co-treatment of CCAT-1 siRNAs and let-7a mimics efficiently relieved Atezolizumab resistance in MDA-MB-231 cells. CONCLUSION The present study revealed a novel PD-L1 regulatory axis via targeting let-7a/c-Myc/CCAT/miR-17-5p. Additionally, it sheds the light on the potential combinational role of CCAT-1 siRNAs and Let-7a mimics in relieving Atezolizumab resistance in TNBC patients.
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Affiliation(s)
- Noha A Selem
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Heba Nafae
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Tamer Manie
- Department of Breast Surgery, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Rana A Youness
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt; Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt.
| | - Mohamed Z Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
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Chaudhuri A, Kumar DN, Dehari D, Patil R, Singh S, Kumar D, Agrawal AK. Endorsement of TNBC Biomarkers in Precision Therapy by Nanotechnology. Cancers (Basel) 2023; 15:cancers15092661. [PMID: 37174125 PMCID: PMC10177107 DOI: 10.3390/cancers15092661] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/05/2023] [Accepted: 05/06/2023] [Indexed: 05/15/2023] Open
Abstract
Breast cancer is a heterogeneous disease which accounts globally for approximately 1 million new cases annually, wherein more than 200,000 of these cases turn out to be cases of triple-negative breast cancer (TNBC). TNBC is an aggressive and rare breast cancer subtype that accounts for 10-15% of all breast cancer cases. Chemotherapy remains the only therapy regimen against TNBC. However, the emergence of innate or acquired chemoresistance has hindered the chemotherapy used to treat TNBC. The data obtained from molecular technologies have recognized TNBC with various gene profiling and mutation settings that have helped establish and develop targeted therapies. New therapeutic strategies based on the targeted delivery of therapeutics have relied on the application of biomarkers derived from the molecular profiling of TNBC patients. Several biomarkers have been found that are targets for the precision therapy in TNBC, such as EGFR, VGFR, TP53, interleukins, insulin-like growth factor binding proteins, c-MET, androgen receptor, BRCA1, glucocorticoid, PTEN, ALDH1, etc. This review discusses the various candidate biomarkers identified in the treatment of TNBC along with the evidence supporting their use. It was established that nanoparticles had been considered a multifunctional system for delivering therapeutics to target sites with increased precision. Here, we also discuss the role of biomarkers in nanotechnology translation in TNBC therapy and management.
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Affiliation(s)
- Aiswarya Chaudhuri
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Dulla Naveen Kumar
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Deepa Dehari
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Rohit Patil
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Sanjay Singh
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
- Department of Pharmaceutics, Babasaheb Bhimrao Ambedkar University (A Central University), Vidya Vihar, Raebareli Road, Lucknow 226025, India
| | - Dinesh Kumar
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Ashish Kumar Agrawal
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi 221005, India
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19
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Ao YQ, Gao J, Wang S, Jiang JH, Deng J, Wang HK, Xu B, Ding JY. Immunotherapy of thymic epithelial tumors: molecular understandings and clinical perspectives. Mol Cancer 2023; 22:70. [PMID: 37055838 PMCID: PMC10099901 DOI: 10.1186/s12943-023-01772-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 04/03/2023] [Indexed: 04/15/2023] Open
Abstract
Immunotherapy has emerged to play a rapidly expanding role in the treatment of cancers. Currently, many clinical trials of therapeutic agents are on ongoing with majority of immune checkpoint inhibitors (ICIs) especially programmed death receptor 1 (PD-1) and its ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1, two main immune checkpoints, are expressed at high levels in thymic epithelial tumors (TETs) and could be predictors of the progression and immunotherapeutic efficacy of TETs. However, despite inspiring efficacy reported in clinical trials and clinical practice, significantly higher incidence of immune-related adverse events (irAEs) than other tumors bring challenges to the administration of ICIs in TETs. To develop safe and effective immunotherapeutic patterns in TETs, understanding the clinical properties of patients, the cellular and molecular mechanisms of immunotherapy and irAEs occurrence are crucial. In this review, the progress of both basic and clinical research on immune checkpoints in TETs, the evidence of therapeutic efficacy and irAEs based on PD-1 /PD-L1 inhibitors in TETs treatment are discussed. Additionally, we highlighted the possible mechanisms underlying irAEs, prevention and management strategies, the insufficiency of current research and some worthy research insights. High PD-1/PD-L1 expression in TETs provides a rationale for ICI use. Completed clinical trials have shown an encouraging efficacy of ICIs, despite the high rate of irAEs. A deeper mechanism understanding at molecular level how ICIs function in TETs and why irAEs occur will help maximize the immunotherapeutic efficacy while minimizing irAEs risks in TET treatment to improve patient prognosis.
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Affiliation(s)
- Yong-Qiang Ao
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Gao
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shuai Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia-Hao Jiang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Deng
- Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai, China
| | - Hai-Kun Wang
- CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Bei Xu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Jian-Yong Ding
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
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20
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Thacker G, Henry S, Nandi A, Debnath R, Singh S, Nayak A, Susnik B, Boone MM, Zhang Q, Kesmodel SB, Gumber S, Das GM, Kambayashi T, Dos Santos CO, Chakrabarti R. Immature natural killer cells promote progression of triple-negative breast cancer. Sci Transl Med 2023; 15:eabl4414. [PMID: 36888695 PMCID: PMC10875969 DOI: 10.1126/scitranslmed.abl4414] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 01/26/2023] [Indexed: 03/10/2023]
Abstract
Natural killer (NK) cells are cytotoxic lymphocytes that accumulate within the tumor microenvironment and are generally considered to be antitumorigenic. Using single-cell RNA sequencing and functional analysis of multiple triple-negative breast cancer (TNBC) and basal tumor samples, we observed a unique subcluster of Socs3highCD11b-CD27- immature NK cells that were present only in TNBC samples. These tumor-infiltrating NK cells expressed a reduced cytotoxic granzyme signature and, in mice, were responsible for activating cancer stem cells through Wnt signaling. NK cell-mediated activation of these cancer stem cells subsequently enhanced tumor progression in mice, whereas depletion of NK cells or Wnt ligand secretion from NK cells by LGK-974 decreased tumor progression. In addition, NK cell depletion or inhibition of their function improved anti-programmed cell death ligand 1 (PD-L1) antibody or chemotherapy response in mice with TNBC. Furthermore, tumor samples from patients with TNBC and non-TNBC revealed that increased numbers of CD56bright NK cells were present in TNBC tumors and were correlated to poor overall survival in patients with TNBC. Together, our findings identify a population of protumorigenic NK cells that may be exploited for both diagnostic and therapeutic strategies to improve outcomes for patients with TNBC.
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Affiliation(s)
- Gatha Thacker
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Samantha Henry
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - Ajeya Nandi
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rahul Debnath
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Snahlata Singh
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anupma Nayak
- Department of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Barbara Susnik
- Department of Pathology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Melinda M Boone
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
| | - Qing Zhang
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Susan B Kesmodel
- DeWitt Daughtry Family Department of Surgery, Division of Surgical Oncology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Sanjeev Gumber
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Gokul M Das
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | - Taku Kambayashi
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Camila O. Dos Santos
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - Rumela Chakrabarti
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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21
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Fu Z, Chen S, Zhu Y, Zhang D, Xie P, Jiao Q, Chi J, Xu S, Xue Y, Lu X, Song X, Cristofanilli M, Gradishar WJ, Kalinsky K, Yin Y, Zhang B, Wan Y. Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity. SCIENCE ADVANCES 2023; 9:eadd6626. [PMID: 36608132 PMCID: PMC9821867 DOI: 10.1126/sciadv.add6626] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 12/06/2022] [Indexed: 05/24/2023]
Abstract
Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that elevation of CD73 levels due to its aberrant turnover is correlated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs). We have identified TRIM21 as an E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8+ T cell function. Replacement of lysine 133, 208, 262, and 321 residues by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM21high/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation.
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Affiliation(s)
- Ziyi Fu
- Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Siqi Chen
- Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yueming Zhu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA
| | - Donghong Zhang
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Ping Xie
- Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Qiao Jiao
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Junlong Chi
- Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Shipeng Xu
- Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yifan Xue
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xinghua Lu
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xinxin Song
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - William J. Gradishar
- Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Kevin Kalinsky
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bin Zhang
- Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yong Wan
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
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22
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Jarroudi OA, Bairi KE, Curigliano G, Afqir S. Immune-Checkpoint Inhibitors: A New Line of Attack in Triple-Negative Breast Cancer. Cancer Treat Res 2023; 188:29-62. [PMID: 38175341 DOI: 10.1007/978-3-031-33602-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Poor prognosis is a distinctive feature of triple-negative breast cancer (TNBC). Chemotherapy has long represented the main and unique treatment for patients with TNBC. Recently, immune checkpoint inhibitors (ICIs) were investigated in several clinical trials and were approved for clinical use in TNBC patients that express programmed cell death protein-1 (PD-1) in combination with chemotherapy in the first-line setting. ICIs are also being investigated in the neoadjuvant and adjuvant settings for TNBC. This chapter aims to discuss different ICIs used to treat all TNBC stages to date.
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Affiliation(s)
- Ouissam Al Jarroudi
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco.
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco.
| | - Khalid El Bairi
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
| | - Giuseppe Curigliano
- European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hematology, University of Milan, Milan, Italy
| | - Said Afqir
- Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco
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23
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Ogier du Terrail J, Leopold A, Joly C, Béguier C, Andreux M, Maussion C, Schmauch B, Tramel EW, Bendjebbar E, Zaslavskiy M, Wainrib G, Milder M, Gervasoni J, Guerin J, Durand T, Livartowski A, Moutet K, Gautier C, Djafar I, Moisson AL, Marini C, Galtier M, Balazard F, Dubois R, Moreira J, Simon A, Drubay D, Lacroix-Triki M, Franchet C, Bataillon G, Heudel PE. Federated learning for predicting histological response to neoadjuvant chemotherapy in triple-negative breast cancer. Nat Med 2023; 29:135-146. [PMID: 36658418 DOI: 10.1038/s41591-022-02155-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 11/23/2022] [Indexed: 01/21/2023]
Abstract
Triple-negative breast cancer (TNBC) is a rare cancer, characterized by high metastatic potential and poor prognosis, and has limited treatment options. The current standard of care in nonmetastatic settings is neoadjuvant chemotherapy (NACT), but treatment efficacy varies substantially across patients. This heterogeneity is still poorly understood, partly due to the paucity of curated TNBC data. Here we investigate the use of machine learning (ML) leveraging whole-slide images and clinical information to predict, at diagnosis, the histological response to NACT for early TNBC women patients. To overcome the biases of small-scale studies while respecting data privacy, we conducted a multicentric TNBC study using federated learning, in which patient data remain secured behind hospitals' firewalls. We show that local ML models relying on whole-slide images can predict response to NACT but that collaborative training of ML models further improves performance, on par with the best current approaches in which ML models are trained using time-consuming expert annotations. Our ML model is interpretable and is sensitive to specific histological patterns. This proof of concept study, in which federated learning is applied to real-world datasets, paves the way for future biomarker discovery using unprecedentedly large datasets.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Camille Franchet
- Institut Universitaire du Cancer de Toulouse (IUCT) Oncopole, Toulouse, France
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24
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Chang JC, Chang HS, Yeh CY, Chang HJ, Cheng WL, Lin TT, Liu CS, Chen ST. Regulation of mitochondrial fusion and mitophagy by intra-tumoral delivery of membrane-fused mitochondria or Midiv-1 enhances sensitivity to doxorubicin in triple-negative breast cancer. Biomed Pharmacother 2022; 153:113484. [PMID: 36076583 DOI: 10.1016/j.biopha.2022.113484] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 11/19/2022] Open
Abstract
Increasing mitochondrial fusion by intra-tumoral grafting of membrane-fused mitochondria created with Pep-1 conjugation (P-Mito) contributes to breast cancer treatment, but it needs to be validated. Using mitochondrial division inhibitor-1 (Mdivi-1, Mdi) to disturb mitochondrial dynamics, we showed that the antitumor action of P-Mito in a mouse model of triple-negative breast cancer depends upon mitochondrial fusion and that Mdi treatment alone is ineffective. P-Mito significantly enhanced Doxorubicin (Dox) sensitivity by inducing mitochondrial fusion and mitophagy, and the same efficiency was also achieved with Mdi by inhibiting mitophagy. Cell death was induced via the p53 pathway and AIF nuclear translocation in the case of P-Mito, versus the caspase-dependent pathway for Mdi. Notably, both mitochondrial treatments reduced oxidative stress and blood vessel density of xenograft tumors, especially P-Mito, which was accompanied by inhibition of nuclear factor kappa-B activation. Furthermore, through enrichment analysis, four microRNAs in serum microvesicles induced by P-Mito caused expression of predicted targets via the PI3K-Akt pathway, and significantly impacted regulation of nuclear processes and myeloid cell differentiation. Clustering of gene-sets implicated a major steroid catabolic network. This study showed diverse roles of mitochondria in breast cancer and revealed effective adjuvant therapy targeting mitochondrial fusion and mitophagy.
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Affiliation(s)
- Jui-Chih Chang
- Center of Regenerative Medicine and Tissue Repair, Institute of ATP, Changhua Christian Hospital, Changhua 50094, Taiwan.
| | - Huei-Shin Chang
- Center of Regenerative Medicine and Tissue Repair, Institute of ATP, Changhua Christian Hospital, Changhua 50094, Taiwan
| | - Cheng-Yi Yeh
- Center of Regenerative Medicine and Tissue Repair, Institute of ATP, Changhua Christian Hospital, Changhua 50094, Taiwan
| | - Hui-Ju Chang
- Center of Regenerative Medicine and Tissue Repair, Institute of ATP, Changhua Christian Hospital, Changhua 50094, Taiwan
| | - Wen-Ling Cheng
- Department of Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan
| | - Ta-Tsung Lin
- Department of Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan
| | - Chin-San Liu
- Department of Vascular and Genomic Center, Changhua Christian Hospital, Changhua 50094, Taiwan; Department of Neurology, Changhua Christian Hospital, Changhua 50094, Taiwan; School of Chinese Medicine, Graduate Institute of Chinese Medicine, Graduate Institute of Integrated Medicine, College of Chinese Medicine, Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung 40447, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
| | - Shou-Tung Chen
- Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 50094, Taiwan; Department of Medical Research, Changhua Christian Hospital, Changhua 50094, Taiwan.
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25
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Bai R, Jia L, Gao Y, Sun X, Chen N, Lv Z, Cui J. Targeted therapy combined with immunotherapy in patients with breast infiltrating ductal carcinoma with axillary lymph node metastasis of metaplastic SCC. Thorac Cancer 2022; 13:2799-2807. [PMID: 35975338 PMCID: PMC9527170 DOI: 10.1111/1759-7714.14602] [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: 06/10/2022] [Revised: 07/18/2022] [Accepted: 07/21/2022] [Indexed: 12/02/2022] Open
Abstract
At present, the clinicopathological features, optimal treatment patterns, and prognosis of breast metaplastic squamous cell carcinoma (SCC) are not fully understood and are still controversial. Here, we report a 56‐year‐old female patient with breast infiltrating ductal carcinoma with axillary lymph node metastasis of metaplastic SCC admitted to our hospital. Their homology was clarified by comparing the gene mutation results of the two lesions, that is, the axillary lymph node lesion was a metastasis of breast metaplastic SCC. We treated the patient with Poly ADP‐ribose Polymerase (PARP) inhibitors in combination with immune checkpoint inhibitors (ICIs) and found that she could achieve clinical benefit from the combination regimen. We reported a successful diagnosis and treatment of this rare refractory disease and reviewed the literature on the characteristics, pathogenesis, and advances in the diagnosis and treatment of breast metaplastic SCC.
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Affiliation(s)
- Rilan Bai
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Lin Jia
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Yangyang Gao
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Xu Sun
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Naifei Chen
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Zheng Lv
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, China
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26
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Green-Tripp G, Nattress C, Halldén G. Targeting Triple Negative Breast Cancer With Oncolytic Adenoviruses. Front Mol Biosci 2022; 9:901392. [PMID: 35813830 PMCID: PMC9263221 DOI: 10.3389/fmolb.2022.901392] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/24/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer (BC) is the most common cancer globally, accounting for 685,000 deaths in 2020. Triple-negative breast cancers (TNBC) lack oestrogen (ER) and progesterone (PR) hormone receptor expression and HER2 overexpression. TNBC represent 10–15% of all BC with high incidence in women under 50-years old that have BRCA mutations, and have a dismal prognosis. African American and Hispanic women are at higher risk partly due to the common occurrence of BRCA mutations. The standard treatment for TNBC includes surgery, radiotherapy, and chemotherapy although, resistance to all standard-of-care therapies eventually develops. It is crucial to identify and develop more efficacious therapeutics with different mechanisms of action to improve on survival in these women. Recent findings with oncolytic adenoviruses (OAds) may generate a new strategy to improve on the outcomes for women afflicted by TNBC and other types of BC. OAds are genetically engineered to selectively lyse, eliminate and recruit the host antitumour immune responses, leaving normal cells unharmed. The most common modifications are deletions in the early gene products including the E1B55 KDa protein, specific regions of the E1A protein, or insertion of tumour-specific promoters. Clinical trials using OAds for various adenocarcinomas have not yet been sufficiently evaluated in BC patients. Preclinical studies demonstrated efficacy in BC cell lines, including TNBC cells, with promising novel adenoviral mutants. Here we review the results reported for the most promising OAds in preclinical studies and clinical trials administered alone and in combination with current standard of care or with novel therapeutics. Combinations of OAds with small molecule drugs targeting the epidermal growth factor receptor (EGFR), androgen receptor (AR), and DNA damage repair by the novel PARP inhibitors are currently under investigation with reported enhanced efficacy. The combination of the PARP-inhibitor Olaparib with OAds showed an impressive anti-tumour effect. The most promising findings to date are with OAds in combination with antibodies towards the immune checkpoints or expression of cytokines from the viral backbone. Although safety and efficacy have been demonstrated in numerous clinical trials and preclinical studies with cancer-selective OAds, further developments are needed to eliminate metastatic lesions, increase immune activation and intratumoural viral spread. We discuss shortcomings of the OAds and potential solutions for improving on patient outcomes.
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Affiliation(s)
- Gabriela Green-Tripp
- Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Callum Nattress
- Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
- Cell Communication Lab, Department of Oncology, University College London Cancer Institute, London, United Kingdom
| | - Gunnel Halldén
- Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
- *Correspondence: Gunnel Halldén,
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27
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Dewi C, Fristiohady A, Amalia R, Khairul Ikram NK, Ibrahim S, Muchtaridi M. Signaling Pathways and Natural Compounds in Triple-Negative Breast Cancer Cell Line. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123661. [PMID: 35744786 PMCID: PMC9227697 DOI: 10.3390/molecules27123661] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 11/16/2022]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, having a poor prognosis and rapid metastases. TNBC is characterized by the absence of estrogen, progesterone, and human epidermal growth receptor-2 (HER2) expressions and has a five-year survival rate. Compared to other breast cancer subtypes, TNBC patients only respond to conventional chemotherapies, and even then, with limited success. Shortages of chemotherapeutic medication can lead to resistance, pressured index therapy, non-selectivity, and severe adverse effects. Finding targeted treatments for TNBC is difficult owing to the various features of cancer. Hence, identifying the most effective molecular targets in TNBC pathogenesis is essential for predicting response to targeted therapies and preventing TNBC cell metastases. Nowadays, natural compounds have gained attention as TNBC treatments, and have offered new strategies for solving drug resistance. Here, we report a systematic review using the database from Pubmed, Science Direct, MDPI, BioScince, Springer, and Nature for articles screening from 2003 to 2022. This review analyzes relevant signaling pathways and the prospect of utilizing natural compounds as a therapeutic agent to improve TNBC treatments in the future.
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Affiliation(s)
- Citra Dewi
- Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia;
- Pharmacy Department, Faculty of Science and Technology, Mandala Waluya University, Kendari 93561, Indonesia
| | - Adryan Fristiohady
- Faculty of Pharmacy, Halu Oleo University, Kampus Hijau Bumi Tridharma, Kendari 93232, Indonesia;
| | - Riezki Amalia
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia;
| | - Nur Kusaira Khairul Ikram
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
| | - Sugeng Ibrahim
- Department of Molecular Biology, Faculty of Medicine, Universitas Katolik Soegijapranata, Semarang 50234, Indonesia;
| | - Muchtaridi Muchtaridi
- Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363, Indonesia;
- Correspondence:
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Ramos JP, Abdel-Salam MAL, Nobre DAB, Glanzmann N, de Souza CP, Leite EA, de Abreu Teles PP, Barbosa AS, Barcelos LS, Dos Reis DC, Cassali GD, de Lima ME, de Castro QJT, Grabe-Guimarães A, da Silva AD, de Souza-Fagundes EM. Acute toxicity and antitumor potential of 1,3,4-trisubstituted-1,2,3-triazole dhmtAc-loaded liposomes on a triple-negative breast cancer model. Arch Pharm (Weinheim) 2022; 355:e2200004. [PMID: 35621705 DOI: 10.1002/ardp.202200004] [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: 01/11/2022] [Revised: 04/28/2022] [Accepted: 05/02/2022] [Indexed: 11/05/2022]
Abstract
For the first time, compounds developed from the 1,2,3-triazole scaffold were evaluated as novel drugs to treat triple-negative breast cancer (TNBC). Four organic salts were idealized as nonclassical bioisosteres of miltefosine, which is used in the topical treatment for skin metastasizing breast carcinoma. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human breast adenocarcinoma cell line and mouse 4T1 cell lines, which are representatives of TNBC. In vitro assays revealed that dhmtAc interferes with cell integrity, confirmed by lactate dehydogenase leakage. Due to its human peripheral blood mononuclear cell (PBMC) toxicity, dhmtAc in vivo studies were carried out with the drug incorporated in a long-circulating and pH-sensitive liposome (SpHL-dhmtAc), and the acute toxicity in BALB/c mice was determined. Free dhmtAc displayed cardiac and pulmonary toxicity after the systemic administration of 5 mg/kg doses. On the other hand, SpHL-dhmtAc displayed no toxicity at 20 mg/kg. The in vivo antitumor effect of SpHL-dhmtAc was investigated using the 4T1 heterotopic murine model. Intravenous administration of SpHL-dhmtAc reduced the tumor volume and weight, without interfering with the body weight, compared with the control group and the dhmtAc free form. The incorporation of the triazole compound in the liposome allowed the demonstration of its anticancer potential. These findings evidenced 1,3,4-trisubstituted-1,2,3-triazole as a promising scaffold for the development of novel drugs with applicability for the treatment of patients with TNBC.
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Affiliation(s)
- Jonas P Ramos
- Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mostafa A L Abdel-Salam
- Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Daniel A B Nobre
- Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Nicolas Glanzmann
- Departamento de Química, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil
| | - Camila P de Souza
- Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Elaine A Leite
- Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Pedro P de Abreu Teles
- Departamento de Patologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Alan S Barbosa
- Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luciola S Barcelos
- Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Diego C Dos Reis
- Departamento de Patologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Geovanni D Cassali
- Departamento de Patologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Maria E de Lima
- Programa de Pós-Graduação em Medicina-Biomedicina, Faculdade Santa Casa de Belo Horizonte, Belo Horizonte, Brazil
| | - Quênia J T de Castro
- Departamento de Farmácia, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, Brazil
| | - Andrea Grabe-Guimarães
- Departamento de Farmácia, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, Brazil
| | - Adilson D da Silva
- Departamento de Química, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil
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Wang X, Zhu X, Li B, Wei X, Chen Y, Zhang Y, Wang Y, Zhang W, Liu S, Liu Z, Zhai W, Zhu P, Gao Y, Chen Z. Intelligent Biomimetic Nanoplatform for Systemic Treatment of Metastatic Triple-Negative Breast Cancer via Enhanced EGFR-Targeted Therapy and Immunotherapy. ACS APPLIED MATERIALS & INTERFACES 2022; 14:23152-23163. [PMID: 35549005 DOI: 10.1021/acsami.2c02925] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, and it is associated with a high recurrence rate, metastatic potential, and poor prognosis. Thus, effective therapeutic strategies for TNBC are urgently required. The epidermal growth factor receptor (EGFR) is considered to be a potential therapeutic target for TNBC. However, there are limitations to the use of targeted therapies, such as afatinib (AFT), particularly drug resistance. Here, we investigated a poly(d,l-lactide-glycolide) (PLGA)-based intelligent bionic nanoplatform, termed AFT/2-BP@PLGA@MD, which combined targeted therapy with immunotherapy. In this platform, PLGA was used to encapsulate 2-bromo-palmitate (2-BP), a palmitoylation inhibitor, to enhance the efficacy of AFT against TNBC cells. PLGA was coated with a cancer cell membrane anchored with a cleavable peptide by matrix metalloproteinase-2 to block programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1). 2-BP significantly enhanced the capacity of AFT to inhibit the proliferation and migration of tumor cells in vitro. Moreover, the tumor cell membrane-coated AFT/2-BP@PLGA@MD nanoparticles exhibited enhanced tumor targeting ability in vivo. The AFT/2-BP@PLGA@MD nanoparticles significantly inhibited the growth and metastasis of 4T1 tumor and prolonged the survival of tumor-bearing mice. The nanoparticles also triggered antitumor immune response. Collectively, we report an effective therapeutic strategy for clinically refractory TNBC.
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Affiliation(s)
- Xiaoxi Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xueqin Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Bingyu Li
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xiuyu Wei
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yalan Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yun Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yan Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Wenyan Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Sijia Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Zimai Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Wenjie Zhai
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yanfeng Gao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, China
| | - Zhenzhen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
- Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou 450001, China
- International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou 450001, China
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Li C, Pan J, Jiang Y, Wu Y, Jin Z, Chen X. Characterization of Pyroptosis-Related Subtypes via RNA-Seq and ScRNA-Seq to Predict Chemo-Immunotherapy Response in Triple-Negative Breast Cancer. Front Genet 2022; 13:788670. [PMID: 35386285 PMCID: PMC8978671 DOI: 10.3389/fgene.2022.788670] [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: 10/03/2021] [Accepted: 02/15/2022] [Indexed: 11/30/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is associated with poor prognosis and invalid therapeutical response to immunotherapy due to biological heterogeneity. There is an urgent need to screen for reliable indices, especially immunotherapy-associated biomarkers that can predict patient outcomes. Pyroptosis, as an inflammation-induced type of programmed cell death, is shown to create a tumor-suppressive environment and improve the chemotherapeutic response in multiple tumors. However, the specific therapeutic effect of pyroptosis in TNBC remains unclear. In this study, we present a consensus clustering by pyroptosis-related signatures of 119 patients with TNBC into two subtypes (clusterA and clusterB) with distinct immunological and prognostic characteristics. First, clusterB, associated with better outcomes, was characterized by a significantly higher pyroptosis-related signature expression, tumor microenvironment prognostic score, and upregulation of immunotherapy checkpoints. A total of 262 differentially expressed genes between the subtypes were further identified and the Ps-score was built using LASSO and COX regression analyses. The external GEO data set demonstrated that cohorts with low Ps-scores consistently had higher expression of pyroptosis-related signatures, immunocyte infiltration levels, and better prognosis. In addition, external immunotherapy and chemotherapy cohorts validated that patients with lower Ps-scores exhibited significant therapeutic response and clinical benefit. Combined with other clinical characteristics, we successfully constructed a nomogram to effectively predict the survival rate of patients with TNBC. Finally, using the scRNA-seq data sets, we validated the landscape of cellular subtypes of TNBC and successfully constructed an miRNA-Ps-score gene interaction network. These findings indicated that the systematic assessment of tumor pyroptosis and identification of Ps-scores has potential clinical implications and facilitates tailoring optimal immunotherapeutic strategies for TNBC.
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Affiliation(s)
- Chenlu Li
- Department of Gastroenterology, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jingjing Pan
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yinyan Jiang
- Department of Hematopathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanzhi Wu
- Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhenlin Jin
- Department of Hematopathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xupeng Chen
- Department of Gastroenterology, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
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Rizzo A, Cusmai A, Acquafredda S, Giovannelli F, Rinaldi L, Misino A, Palmiotti G. KEYNOTE-522, IMpassion031 and GeparNUEVO: changing the paradigm of neoadjuvant immune checkpoint inhibitors in early triple-negative breast cancer. Future Oncol 2022; 18:2301-2309. [PMID: 35378995 DOI: 10.2217/fon-2021-1647] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Stage I-III triple-negative breast cancer accounts for approximately 15-20% of new diagnoses of early breast cancer. Novel systemic treatment options have recently been assessed as part of the neoadjuvant approach, such as the addition of immune checkpoint inhibitors to cytotoxic chemotherapy. However, several questions remain unanswered, including the identification of predictors of response to immunotherapy in this setting, and further efforts aimed at identifying reliable predictors and clarifying the effective role of PD-L1 status, tumor mutational burden, tumor-infiltrating lymphocytes and other biomarkers are warranted. Herein we will provide an overview of recent clinical studies of neoadjuvant immune checkpoint inhibitors in patients with triple-negative breast cancer, especially focusing on the recently presented and published KEYNOTE-522, IMpassion031 and GeparNUEVO trials.
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Affiliation(s)
- Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico 'Don Tonino Bello', IRCCS Istituto Tumori 'Giovanni Paolo II', Viale Orazio Flacco 65, Bari, 70124, Italy
| | - Antonio Cusmai
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico 'Don Tonino Bello', IRCCS Istituto Tumori 'Giovanni Paolo II', Viale Orazio Flacco 65, Bari, 70124, Italy
| | - Silvana Acquafredda
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico 'Don Tonino Bello', IRCCS Istituto Tumori 'Giovanni Paolo II', Viale Orazio Flacco 65, Bari, 70124, Italy
| | - Francesco Giovannelli
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico 'Don Tonino Bello', IRCCS Istituto Tumori 'Giovanni Paolo II', Viale Orazio Flacco 65, Bari, 70124, Italy
| | - Lucia Rinaldi
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico 'Don Tonino Bello', IRCCS Istituto Tumori 'Giovanni Paolo II', Viale Orazio Flacco 65, Bari, 70124, Italy
| | - Andrea Misino
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico 'Don Tonino Bello', IRCCS Istituto Tumori 'Giovanni Paolo II', Viale Orazio Flacco 65, Bari, 70124, Italy
| | - Gennaro Palmiotti
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico 'Don Tonino Bello', IRCCS Istituto Tumori 'Giovanni Paolo II', Viale Orazio Flacco 65, Bari, 70124, Italy
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Kim NI, Park MH, Cho N, Lee JS. Comparison of the Clinicopathologic Features and T-Cell Infiltration of B7-H3 and B7-H4 Expression in Triple-negative Breast Cancer Subtypes. Appl Immunohistochem Mol Morphol 2022; 30:246-256. [PMID: 35384874 PMCID: PMC8989634 DOI: 10.1097/pai.0000000000001001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 11/11/2021] [Indexed: 11/26/2022]
Abstract
Previously we revealed an upregulated expression of B7-H3 and B7-H4 mRNA and protein in breast cancer, including triple-negative breast cancer (TNBC). However, little is known regarding the clinical impact and value of B7-H3 and B7-H4 in TNBC subtypes. Thus, this study evaluated the clinicopathologic effects of B7-H3 and B7-H4 mRNA and protein expression according to the TNBC subtypes. RNAscope in situ hybridization and immunohistochemistry of B7-H3 and B7-H4 was done for 186 TNBC samples using tissue microarray. Immunohistochemistry was also performed for TNBC molecular subtype-surrogate markers, CD3, and CD8. TNBCs were classified into basal-like (BL) (64.5%), luminal androgen receptor (10.8%), and unclassifiable (24.7%) subtypes. Tumor B7-H4 mRNA expression was associated with younger age at the initial diagnosis and with molecular TNBC subtypes. Expression of B7-H3 mRNA and protein in the tumor cells was negatively correlated with CD3+ and CD8+ T-cell infiltration density in the tumor and/or stromal region of TNBCs and their subtypes. High stromal B7-H3 mRNA expression was associated with poor disease-free and overall survival in the TNBCs and with overall survival in the unclassifiable subtype. Stromal B7-H3 mRNA expression was independently associated with overall survival and disease-free survival in the TNBCs and BL subtype, respectively. Our results indicate the importance of the stromal expression of B7-H3 mRNA as a prognostic factor in the TNBCs and BL subtype. The inverse relationship between B7-H3 expression and CD3+ and CD8+ T-lymphocyte infiltration represents a promising target for immunotherapy for the TNBCs, especially the BL subtype.
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Affiliation(s)
| | - Min Ho Park
- Surgery, Chonnam National University Medical School
| | - NamKi Cho
- College of Pharmacy, Chonnam National University, Gwangju, South Korea
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Wang L, Sun W, Zhang G, Huo J, Tian Y, Zhang Y, Yang X, Liu Y. T-cell activation is associated with high-grade serous ovarian cancer survival. J Obstet Gynaecol Res 2022; 48:2189-2197. [PMID: 35334503 DOI: 10.1111/jog.15234] [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: 11/04/2021] [Revised: 03/05/2022] [Accepted: 03/12/2022] [Indexed: 11/30/2022]
Abstract
AIM High-grade serous ovarian cancer (HGSOC) is an aggressive disease that is largely resistant to today's immunotherapies. Here, we aimed to investigate the prognostic significance of CTLA4, PD-1, and T-cell activation status in HGSOC. METHODS Using a publicly accessed microarray dataset including 260 HGSOC samples, we calculated Kaplan-Meier survival curves for overall survival (OS), evaluated associations with multivariate Cox regression models to evaluate the associations, and summarized using a hazard ratio (HR). The correlations between PD-1 gene expression and that of other genes were calculated by Pearson correlation. RESULTS Multivariate survival analyses showed that high PD-1 expression but not CTLA4 was associated with longer OS (HR = 0.69; 95% confidence interval [CI] = 0.52-0.91; p = 0.01), and that higher T-cell activation score was associated with better outcome (HR = 0.74; 95% confidence interval [CI] = 0.58-0.95; p = 0.02). The top three PD-1 highly correlated genes were SIRPG (r = 0.90, p < 2E-16), FASL (r = 0.89, p < 2E-16), and CD8a (r = 0.87, p < 2E-16). HGSOC patients' OS is positively associated T-cell activation score and PD-1 expression but not CTLA4. CONCLUSION T cell activation score may serve as a candidate for personalized immunotherapy in HGSOC. The application of anti-PD-1 therapy to HGSOC should be cautious.
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Affiliation(s)
- Lei Wang
- Microbiology and Immunology Department, Cangzhou Medical College, Cangzhou, P.R. China
| | - Wenjie Sun
- Science and Technology Experiment Center, Cangzhou Medical College, Cangzhou, P.R. China
| | - Guoan Zhang
- Science and Technology Experiment Center, Cangzhou Medical College, Cangzhou, P.R. China
| | - Jingrui Huo
- Science and Technology Experiment Center, Cangzhou Medical College, Cangzhou, P.R. China
| | - Yi Tian
- Microbiology and Immunology Department, Cangzhou Medical College, Cangzhou, P.R. China
| | - Yan Zhang
- Science and Technology Experiment Center, Cangzhou Medical College, Cangzhou, P.R. China
| | - Xiaohui Yang
- Science and Technology Experiment Center, Cangzhou Medical College, Cangzhou, P.R. China
| | - Yingfu Liu
- Cangzhou Nanobody Technology Innovation Center, Cangzhou Medical College, Cangzhou, P.R. China
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Li Y, Chen Z, Gu L, Duan Z, Pan D, Xu Z, Gong Q, Li Y, Zhu H, Luo K. Anticancer nanomedicines harnessing tumor microenvironmental components. Expert Opin Drug Deliv 2022; 19:337-354. [PMID: 35244503 DOI: 10.1080/17425247.2022.2050211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Small-molecular drugs are extensively used in cancer therapy, while they have issues of nonspecific distribution and consequent side effects. Nanomedicines that incorporate chemotherapeutic drugs have been developed to enhance the therapeutic efficacy of these drugs and reduce their side effects. One of the promising strategies is to prepare nanomedicines by harnessing the unique tumor microenvironment (TME). AREAS COVERED The TME contains numerous cell types that specifically express specific antibodies on the surface including tumor vascular endothelial cells, tumor-associated adipocytes, tumor-associated fibroblasts, tumor-associated immune cells and cancer stem cells. The physicochemical environment is characterized with a low pH, hypoxia, and a high redox potential resulting from tumor-specific metabolism. The intelligent nanomedicines can be categorized into two groups: the first group which is rapidly responsive to extracellular chemical/biological factors in the TME and the second one which actively and/or specifically targets cellular components in the TME. EXPERT OPINION In this paper, we review recent progress of nanomedicines by harnessing the TME and illustrate the principles and advantages of different strategies for designing nanomedicines, which are of great significance for exploring novel nanomedicines or translating current nanomedicines into clinical practice. We will discuss the challenges and prospects of preparing nanomedicines to utilize or alter the TME for achieving effective, safe anticancer treatment.
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Affiliation(s)
- Yinggang Li
- Laboratory of Stem Cell Biology, Department of Cardiology, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhonglan Chen
- Laboratory of Stem Cell Biology, Department of Cardiology, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.,Chinese Evidence-Based Medicine Centre, Cochrane China Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lei Gu
- Laboratory of Stem Cell Biology, Department of Cardiology, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhengyu Duan
- Laboratory of Stem Cell Biology, Department of Cardiology, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dayi Pan
- Laboratory of Stem Cell Biology, Department of Cardiology, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhuping Xu
- Laboratory of Stem Cell Biology, Department of Cardiology, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiyong Gong
- Laboratory of Stem Cell Biology, Department of Cardiology, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.,Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China
| | - Youping Li
- Chinese Evidence-Based Medicine Centre, Cochrane China Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hongyan Zhu
- Laboratory of Stem Cell Biology, Department of Cardiology, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kui Luo
- Laboratory of Stem Cell Biology, Department of Cardiology, Department of Radiology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.,Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China
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35
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Chen Y, Wang L, Zheng M, Zhu C, Wang G, Xia Y, Blumenthal EJ, Mao W, Wan Y. Engineered extracellular vesicles for concurrent Anti-PDL1 immunotherapy and chemotherapy. Bioact Mater 2022; 9:251-265. [PMID: 34820569 PMCID: PMC8586263 DOI: 10.1016/j.bioactmat.2021.07.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 have been approved for the treatment of a variety of cancers. However, the efficacy of antibody-based ICIs could be further improved by mitigating anti-drug antibodies, proteolytic cleavage, and on-target off-tumor toxicity. One strategy for accomplishing this is through the use of extracellular vesicles (EVs), cell derived submicron vesicles with many unique properties. We constructed an engineered MDA-MB-231 cell line for harvesting EVs. This was accomplished by overexpressing a high-affinity variant human PD-1 protein (havPD-1), while simultaneously knocking out intrinsic PD-L1 and beta-2 microglobulin. The engineered havPD-1 EVs reduced PD-L1 overexpressing cancer cell proliferation and induced cellular apoptosis. Moreover, the EVs were shown to efficiently block PD-L1 mediated T cell suppression. Meanwhile antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not observed. The havPD-1 EVs treatment resulted in robust anti-tumor activity in both preventative co-implantation and therapeutic xenograft tumor models reconstituted with human T cells. The efficacy of the havPD-1 EVs was shown to be comparable to clinical anti-PD1 monoclonal antibodies. Additionally, loading the havPD-1 EVs with a potent PARP inhibitor was shown to further augment treatment efficacy. In brief, the engineered universal EVs harboring havPD-1 proteins can be used for cancer concurrent immunotherapy and chemotherapy.
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Affiliation(s)
- Yundi Chen
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY, 13902, United States
| | - Lixue Wang
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY, 13902, United States
- Department of Radiotherapy, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210003, China
| | - Mingfeng Zheng
- Department of Cardiothoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China
| | - Chuandong Zhu
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY, 13902, United States
- Department of Radiotherapy, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210003, China
| | - Guosheng Wang
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY, 13902, United States
| | - Yiqiu Xia
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, United States
| | - Ethan J. Blumenthal
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY, 13902, United States
| | - Wenjun Mao
- Department of Cardiothoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China
| | - Yuan Wan
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY, 13902, United States
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Qureshi S, Chan N, George M, Ganesan S, Toppmeyer D, Omene C. Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: The Search for the Optimal Biomarker. Biomark Insights 2022; 17:11772719221078774. [PMID: 35221668 PMCID: PMC8874164 DOI: 10.1177/11772719221078774] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 01/04/2022] [Indexed: 12/14/2022] Open
Abstract
Triple negative breast cancer (TNBC) is a high-risk and aggressive malignancy characterized by the absence of estrogen receptors (ER) and progesterone receptors (PR) on the surface of malignant cells, and by the lack of overexpression of human epidermal growth factor 2 (HER2). It has limited therapeutic options compared to other subtypes of breast cancer. There is now a growing body of evidence on the role of immunotherapy in TNBC, however much of the data from clinical trials is conflicting and thus, challenging for clinicians to integrate the data into clinical practice. Landmark phase III trials using immunotherapy in the early-stage neoadjuvant setting concluded that the addition of immunotherapy to chemotherapy improved the pathologic complete response (pCR) rate compared to chemotherapy with placebo while others found no significant improvement in pCR. Phase III trials have investigated the utility of immunotherapy in previously untreated metastatic TNBC, and these studies have similarly arrived at inconsistent conclusions. Some studies showed no benefit while others demonstrated a clinically significant improvement in overall survival in the PD-L1 positive population. It is not yet clear which biomarkers are most useful, and assays for these biomarkers have not been standardized. Given the often serious and severe side effects of immunotherapy, it is important and necessary to identify predictive biomarkers of response and resistance in order to enhance patient selection. In this review, we will discuss both the challenges of traditional biomarkers and the opportunities of emerging biomarkers for patient selection.
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Affiliation(s)
- Sadaf Qureshi
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Nancy Chan
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Mridula George
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Shridar Ganesan
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Deborah Toppmeyer
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
| | - Coral Omene
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA
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Hamm C, Fifield BA, Kay A, Kulkarni S, Gupta R, Mathews J, Ferraiuolo RM, Al-Wahsh H, Mailloux E, Hussein A, Porter LA. A prospective phase II clinical trial identifying the optimal regimen for carboplatin plus standard backbone of anthracycline and taxane-based chemotherapy in triple negative breast cancer. Med Oncol 2022; 39:49. [PMID: 35103812 DOI: 10.1007/s12032-021-01637-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 12/23/2021] [Indexed: 12/31/2022]
Abstract
Addition of platinums to combination chemotherapy for triple negative breast cancer (TNBC) has shown efficacy and is increasingly accepted in the clinic, yet optimal delivery is unknown. A prospective clinical trial with TNBC patients was conducted to determine the optimal chemotherapy regimen to deliver carboplatin with standard dose dense ACT. Tissue microarray was conducted to isolate markers indicative of response to treatment. 90 TNBC patients were enrolled onto our trial. The most successful version placed the carboplatin on the second and final paclitaxel treatment with liberal hematological parameters. Our final regimen had the lowest grade 3 or 4 toxicities, no delays, no dose reductions of carboplatin, and 32% reduction in paclitaxel doses. Stage I (AJCC7) patients did well with carboplatin-based chemotherapy with zero relapse rate. Reduction in protein levels of androgen receptor and PD-L1 were found to be potential indicators of patient relapse. We have optimized a protocol for the addition of carboplatin to standard of care chemotherapy in TNBC patients. Early data indicates reduced protein levels of androgen receptor and PD-L1 as indicators of response to treatment.Trial registration This trial was registered at Canadian Cancer Trials. http://www.canadiancancertrials.ca/.
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Affiliation(s)
- Caroline Hamm
- University of Windsor, Windsor, ON, N9B 3P4, Canada.
- Western University, Windsor, ON, N9B 3P4, Canada.
- Windsor Cancer Research Group, Windsor, ON, N9B 3P4, Canada.
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
- WE-SPARK Health Institute, Windsor, ON, N9B 3P4, Canada.
| | - Bre-Anne Fifield
- University of Windsor, Windsor, ON, N9B 3P4, Canada
- Windsor Cancer Research Group, Windsor, ON, N9B 3P4, Canada
| | - Amin Kay
- University of Windsor, Windsor, ON, N9B 3P4, Canada
- Western University, Windsor, ON, N9B 3P4, Canada
| | - Swati Kulkarni
- University of Windsor, Windsor, ON, N9B 3P4, Canada
- Western University, Windsor, ON, N9B 3P4, Canada
- Windsor Cancer Research Group, Windsor, ON, N9B 3P4, Canada
- WE-SPARK Health Institute, Windsor, ON, N9B 3P4, Canada
| | - Rasna Gupta
- University of Windsor, Windsor, ON, N9B 3P4, Canada
- Western University, Windsor, ON, N9B 3P4, Canada
- Windsor Cancer Research Group, Windsor, ON, N9B 3P4, Canada
| | - John Mathews
- University of Windsor, Windsor, ON, N9B 3P4, Canada
- Western University, Windsor, ON, N9B 3P4, Canada
| | - Rosa-Maria Ferraiuolo
- Windsor Cancer Research Group, Windsor, ON, N9B 3P4, Canada
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | | | - Emily Mailloux
- University of Windsor, Windsor, ON, N9B 3P4, Canada
- Windsor Cancer Research Group, Windsor, ON, N9B 3P4, Canada
| | | | - Lisa A Porter
- University of Windsor, Windsor, ON, N9B 3P4, Canada.
- Windsor Cancer Research Group, Windsor, ON, N9B 3P4, Canada.
- WE-SPARK Health Institute, Windsor, ON, N9B 3P4, Canada.
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38
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St-Denis-Bissonnette F, Khoury R, Mediratta K, El-Sahli S, Wang L, Lavoie JR. Applications of Extracellular Vesicles in Triple-Negative Breast Cancer. Cancers (Basel) 2022; 14:451. [PMID: 35053616 PMCID: PMC8773485 DOI: 10.3390/cancers14020451] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 02/01/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive and refractory subtype of breast cancer, often occurring in younger patients with poor clinical prognosis. Given the current lack of specific targets for effective intervention, the development of better treatment strategies remains an unmet medical need. Over the last decade, the field of extracellular vesicles (EVs) has grown tremendously, offering immense potential for clinical diagnosis/prognosis and therapeutic applications. While TNBC-EVs have been shown to play an important role in tumorigenesis, chemoresistance and metastasis, they could be repurposed as potential biomarkers for TNBC diagnosis and prognosis. Furthermore, EVs from various cell types can be utilized as nanoscale drug delivery systems (NDDS) for TNBC treatment. Remarkably, EVs generated from specific immune cell subsets have been shown to delay solid tumour growth and reduce tumour burden, suggesting a new immunotherapy approach for TNBC. Intrinsically, EVs can cross the blood-brain barrier (BBB), which holds great potential to treat the brain metastases diagnosed in one third of TNBC patients that remains a substantial clinical challenge. In this review, we present the most recent applications of EVs in TNBC as diagnostic/prognostic biomarkers, nanoscale drug delivery systems and immunotherapeutic agents, as well as discuss the associated challenges and future directions of EVs in cancer immunotherapy.
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Affiliation(s)
- Frederic St-Denis-Bissonnette
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (F.S.-D.-B.); (R.K.); (K.M.); (S.E.-S.)
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON K1A 0K9, Canada
| | - Rachil Khoury
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (F.S.-D.-B.); (R.K.); (K.M.); (S.E.-S.)
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Karan Mediratta
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (F.S.-D.-B.); (R.K.); (K.M.); (S.E.-S.)
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Sara El-Sahli
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (F.S.-D.-B.); (R.K.); (K.M.); (S.E.-S.)
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (F.S.-D.-B.); (R.K.); (K.M.); (S.E.-S.)
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Jessie R. Lavoie
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (F.S.-D.-B.); (R.K.); (K.M.); (S.E.-S.)
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON K1A 0K9, Canada
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39
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Fan Y, He S. The Characteristics of Tumor Microenvironment in Triple Negative Breast Cancer. Cancer Manag Res 2022; 14:1-17. [PMID: 35018117 PMCID: PMC8740624 DOI: 10.2147/cmar.s316700] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 09/06/2021] [Indexed: 12/13/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a special subtype of breast cancer, accounting for 10-20% of breast cancers with high intrinsic heterogeneity. Its unique immune microenvironment, including high expression of vascular endothelial growth factors, tumor infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and other molecules that promote the growth and migration of tumor cells, has been shown to play a dual role in the occurrence, growth, and metastasis of TNBC. Understanding the TNBC microenvironment is of great significance for the prognosis and treatment of TNBC. In this article, we describe the composition and function of immune cells in the TNBC microenvironment and summarize the major cytokine growth factors and chemokines in the TNBC microenvironment. Finally, we discuss the progress of TNBC, cytokine-induced killer cell therapy, and immune checkpoint therapy.
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Affiliation(s)
- Yiqi Fan
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People’s Republic of China
| | - Shuai He
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People’s Republic of China
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40
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Hu Y, Burkard ME. Classes of therapeutics to amplify the immune response. Breast Cancer Res Treat 2022; 191:277-289. [PMID: 34787761 PMCID: PMC11646685 DOI: 10.1007/s10549-021-06369-3] [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: 06/10/2021] [Accepted: 08/18/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE Conventional chemotherapies are a mainstay for metastatic breast cancers, though durable response is rare. Immunotherapies promise long-term responses thorough immune activation but have been underwhelming in breast cancer relative to other cancer types. Here, we review the mechanisms of existing strategies including chemotherapies and how they may cause breast cancers to become immunogenic to identify potential biomarkers for combinations of conventional and immunotherapies. CONCLUSION Mechanistic considerations should inform biomarker development and patient selection for therapeutic combinations of drugs to combine with immune-checkpoint inhibitors.
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Affiliation(s)
- Yang Hu
- Department of Medicine, Hematology/Oncology and Palliative Care, University of Wisconsin-Madison, Madison, WI, 53705, USA
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA
- UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Medical Scientist Training Program, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Mark E Burkard
- Department of Medicine, Hematology/Oncology and Palliative Care, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- Wisconsin Institutes for Medical Research, School of Medicine and Public Health, University of Wisconsin, 1111 Highland Avenue, Madison, WI, 53705, USA.
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41
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Rizzo A, Ricci AD, Lanotte L, Lombardi L, Di Federico A, Brandi G, Gadaleta-Caldarola G. Immune-based combinations for metastatic triple negative breast cancer in clinical trials: current knowledge and therapeutic prospects. Expert Opin Investig Drugs 2021; 31:557-565. [PMID: 34802383 DOI: 10.1080/13543784.2022.2009456] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitor (ICI) monotherapy appears to be effective in a small cohort of patients with metastatic triple negative breast cancer (mTNBC). This supports the exploration of strategies for increasing the efficacy of immunotherapy. To enhance overall response and clinical outcomes, several immune-based combinations are being investigated. AREAS COVERED The authors present a synopsis of current, state-of-art immune-based combinations in this setting and reflect on future possibilities. They shed light on recently presented and published clinical trials and ongoing studies. A literature search was conducted in October 2021; in addition, abstracts of international cancer meetings were reviewed. EXPERT OPINION Clinical trials suggest that ICI monotherapy could be beneficial in a minority of mTNBC patients; conversely, several immune-based combinations have reported notable results in recently presented or published studies. Some of these combination strategies have been approved for mTNBC - as in the case of chemoimmunotherapy in PD-L1 positive patients. Numerous trials are investigating novel ICI-based combinations and their results are eagerly awaited.
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Affiliation(s)
- Alessandro Rizzo
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italia.,Medical Oncology Unit, "Mons. R. Dimiccoli" Hospital, Barletta (BT), ASL BT, Barletta, Italy
| | - Angela Dalia Ricci
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italia.,Medical Oncology Unit, "Mons. R. Dimiccoli" Hospital, Barletta (BT), ASL BT, Barletta, Italy
| | - Laura Lanotte
- Medical Oncology Unit, "Mons. R. Dimiccoli" Hospital, Barletta (BT), ASL BT, Barletta, Italy
| | - Lucia Lombardi
- Medical Oncology Unit, "Mons. R. Dimiccoli" Hospital, Barletta (BT), ASL BT, Barletta, Italy
| | | | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italia
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Lin X, Chen H, Xie Y, Zhou X, Wang Y, Zhou J, Long S, Hu Z, Zhang S, Qiu W, Zeng Z, Liu L. Combination of CTLA-4 blockade with MUC1 mRNA nanovaccine induces enhanced anti-tumor CTL activity by modulating tumor microenvironment of triple negative breast cancer. Transl Oncol 2021; 15:101298. [PMID: 34875483 PMCID: PMC8652013 DOI: 10.1016/j.tranon.2021.101298] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 11/16/2022] Open
Abstract
The immunosuppressive tumor microenvironment (TME) is the main reason for the failure of many immunotherapies that directly stimulate anti-tumor immune response. Anti-CTLA-4 antibody may reduce effector regulatory T (Treg) cell numbers and their suppressive activity in the TME. We have previously reported that combination of anti-CTLA-4 antibody with MUC1 mRNA nanovaccine may mutually enhance each single treatment. But the enhancement mechanism of therapeutic efficacy of MUC1 mRNA nanovaccine plus anti-CTLA-4 monoclonal antibody (mAb) is unknown. In this study, anti-tumor CTL activity induced by combination of CTLA-4 Blockade with MUC1 mRNA nanovaccine and immunosuppressive factors in the TME of triple negative breast cancer were investigated. The results demonstrated that combined therapy with nanovaccine and anti-CTLA-4 mAb could induce stronger anti-tumor CTL response than each monotherapy, result in significantly decreased numbers of myeloid-derived suppressor cells (MDSC), Treg cells, tumor-associated fibroblasts (TAFs) and tumor vasculature in the TME, downregulated levels of interleukin-6, tumor necrosis factor-α and transforming growth factor-β, and significantly upregulated levels of IFN-γ and interleukin-12 as well as increased number of CD8+ T cell, and appear more effective than either nanovaccine or anti-CTLA-4 mAb alone at increasing level of apoptosis in tumor cells. In addition, combination immunotherapy could significantly downregulated the signal transducer and activator of transcription 3 (STAT3) signal pathway. Therefore, it can be concluded that combination of CTLA-4 blockade with MUC1 mRNA nanovaccine enhances anti-tumor cytotoxic T-lymphocyte activity by reducing immunosuppressive TME and inhibiting tumor-promoting STAT3 signaling pathway.
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Affiliation(s)
- Xuan Lin
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Hedan Chen
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Ying Xie
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Xue Zhou
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Yun Wang
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China; School of Basic Medical Science, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Jing Zhou
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Shiqi Long
- School of Basic Medical Science, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Zuquan Hu
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Shichao Zhang
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Wei Qiu
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Zhu Zeng
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, China; School of Basic Medical Science, Guizhou Medical University, Guiyang, Guizhou 550025, China.
| | - Lina Liu
- Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Medical Biotechnology, School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou 550025, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, China.
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43
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Selem NA, Youness RA, Gad MZ. What is beyond LncRNAs in breast cancer: A special focus on colon cancer-associated Transcript-1 (CCAT-1). Noncoding RNA Res 2021; 6:174-186. [PMID: 34938928 PMCID: PMC8666458 DOI: 10.1016/j.ncrna.2021.11.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 02/07/2023] Open
Abstract
Long non-coding RNAs (LncRNAs) play a vital role in the process of malignant transformation. In breast cancer (BC), lncRNAs field is currently under intensive investigations. Yet, the role of lncRNAs as promising diagnostic and/or prognostic biomarkers and as therapeutic target/tool among BC patients still needs a special focus from the biomedical scientists. In BC, triple negative breast cancer patients (TNBC) are the unlucky group as they are always represented with the worst prognosis and the highest mortality rates. For that reason, a special focus on TNBC and associated lncRNAs was addressed in this review. Colon cancer-associated transcript 1 (CCAT-1) is a newly discovered oncogenic lncRNA that has been emerged as a vital biomarker for diagnosis, prognosis and therapeutic interventions in multiple malignancies and showed differential expression among TNBC patients. In this review, the authors shed the light onto the general role of lncRNAs in BC and the specific functional activities, molecular mechanisms, competing endogenous ncRNA role of CCAT-1 in TNBC.
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Affiliation(s)
- Noha A. Selem
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
| | - Rana A. Youness
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
- School of Life and Medical Sciences, University of Hertfordshire Hosted By Global Academic Foundation, New Administrative Capital, 11586, Cairo, Egypt
| | - Mohamed Z. Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt
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Rizzo A, Ricci AD. Biomarkers for breast cancer immunotherapy: PD-L1, TILs, and beyond. Expert Opin Investig Drugs 2021; 31:549-555. [PMID: 34793275 DOI: 10.1080/13543784.2022.2008354] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs) have recently entered into the therapeutic scenario of metastatic breast cancer. However, only a proportion of patients benefit from ICIs and immune-based combinations, so the identification of reliable predictors of response remains an unmet need. AREAS COVERED We discuss potential predictors of response to ICIs in breast cancer, including PD-L1 expression, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and several other biomarkers and suggest future directions of research in this setting. A literature search was conducted in October 2021 of Pubmed/Medline, Cochrane library and Scopus databases; in addition, abstract of international cancer meetings were reviewed. EXPERT OPINION In terms of predictors of response to immunotherapy in TNBC patients, several biomarkers are being evaluated. Valuable data on predictive biomarkers have recently emerged, including host-related factors, immune-related cells, and protein and genetic markers. Data supporting immunotherapy in the metastatic triple-negative breast cancer setting are not concordant, but there have been some positive phase III trials including IMpassion130 and KEYNOTE-355. Phase II and III (neo)adjuvant trials are supportive of this therapeutic strategy. Further investigations are warranted in this challenging area.
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Affiliation(s)
- Alessandro Rizzo
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
| | - Angela Dalia Ricci
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
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45
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Li Y, Zhan Z, Yin X, Fu S, Deng X. Targeted Therapeutic Strategies for Triple-Negative Breast Cancer. Front Oncol 2021; 11:731535. [PMID: 34778045 PMCID: PMC8581040 DOI: 10.3389/fonc.2021.731535] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 10/12/2021] [Indexed: 12/13/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, which is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression and the absence of human epidermal growth factor receptor 2 (HER2) expression/amplification. Conventional chemotherapy is the mainstay of systemic treatment for TNBC. However, lack of molecular targeted therapies and poor prognosis of TNBC patients have prompted a great effort to discover effective targets for improving the clinical outcomes. For now, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi's) and immune checkpoint inhibitors have been approved for the treatment of TNBC. Moreover, agents that target signal transduction, angiogenesis, epigenetic modifications, and cell cycle are under active preclinical or clinical investigations. In this review, we highlight the current major developments in targeted therapies of TNBC, with some descriptions about their (dis)advantages and future perspectives.
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Affiliation(s)
- Ying Li
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, China.,Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, China
| | - Zhijun Zhan
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, China.,Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, China
| | - Xuemin Yin
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, China.,Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, China
| | - Shujun Fu
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, China.,Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, China
| | - Xiyun Deng
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Department of Pathophysiology, Hunan Normal University School of Medicine, Changsha, China.,Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, China
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Bezrookove V, Patino JM, Nosrati M, Desprez PY, McAllister S, Soroceanu L, Baron A, Osorio R, Kashani-Sabet M, Dar AA. Niraparib Suppresses Cholangiocarcinoma Tumor Growth by Inducing Oxidative and Replication Stress. Cancers (Basel) 2021; 13:cancers13174405. [PMID: 34503215 PMCID: PMC8430987 DOI: 10.3390/cancers13174405] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/22/2021] [Accepted: 08/27/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary Cholangiocarcinoma (CCA) is a rare and highly aggressive tumor with limited therapeutic options, thus underscoring the need to develop novel therapeutic approaches. We analyzed a publicly available CCA patient database to identify mutations in DNA damage response (DDR) genes. Mutations in DDR genes were prevalent, thus rendering these tumors potentially susceptible to poly-ADP-ribose polymerase (PARP) inhibition. PARP genes are critical to DNA repair and genomic stability. The role of PARP inhibitors in CCA was investigated by employing a series of in vitro functional assays and in vivo patient-derived xenograft models. This study highlights the therapeutic potential of PARP inhibitors alone or in combination with the chemotherapeutic agent gemcitabine for the treatment of CCA. Abstract Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer, an aggressive malignancy with limited therapeutic options. PARP (poly (ADP-ribose) polymerase) 1 and 2 are important for deoxyribonucleotide acid (DNA) repair and maintenance of genomic stability. PARP inhibitors (PARPi) such as niraparib have been approved for different malignancies with genomic alteration in germline BRCA and DNA damage response (DDR) pathway genes. Genomic alterations were analyzed in DDR genes in CCA samples employing The Cancer Genome Atlas (TCGA) database. Mutations were observed in various DDR genes, and 35.8% cases had alterations in at least one of three genes (ARID1A, BAP1 and ATM), suggesting their susceptibility to PARPi. Niraparib treatment suppressed cancer cell viability and survival, and also caused G2/M cell cycle arrest in patient-derived xenograft cells lines (PDXC) and established CCA cells harboring DDR gene mutations. PARPi treatment also induced apoptosis and caspase3/7 activity in PDXC and CCA cell lines, and substantially reduced expression of BCL2, BCL-XL and MCL1 proteins. Niraparib caused a significant increase in oxidative stress, and induced activation of DNA damage markers, phosphorylation of CHK2 and replication fork stalling. Importantly, niraparib, in combination with gemcitabine, produced sustained and robust inhibition of tumor growth in vivo in a patient-derived xenograft (PDX) model more effectively than either treatment alone. Furthermore, tissue samples from mice treated with niraparib and gemcitabine display significantly lower expression levels of pHH3 and Ki-67, which are a mitotic and proliferative marker, respectively. Taken together, our results indicate niraparib as a novel therapeutic agent alone or in combination with gemcitabine for CCA.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Altaf A. Dar
- Correspondence: ; Tel.: +1-415-600-5909; Fax: +1-415-600-1719
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Immunotherapy Treatment for Triple Negative Breast Cancer. Pharmaceuticals (Basel) 2021; 14:ph14080763. [PMID: 34451860 PMCID: PMC8401402 DOI: 10.3390/ph14080763] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 12/17/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. Local recurrence rate after standard therapy in the early breast cancer setting can be upwards to 72% in 5 years, and in the metastatic setting, the 5-year overall survival is 12%. Due to the lack of receptor expression, there has been a paucity of targeted therapeutics available, with chemotherapy being the primary option for systemic treatment in both the neoadjuvant and metastatic setting. More recently, immunotherapy has revolutionized the landscape of cancer treatment, particularly immune checkpoint inhibitor (ICI) therapy, with FDA approval in over 20 types of cancer since 2011. Compared to other cancer types, breast cancer has been traditionally thought of as being immunologically cold; however, TNBC has demonstrated the most promise with immunotherapy use, a timely discovery due to its lack of targeted therapy options. In this review, we summarize the trials using checkpoint therapy in early and metastatic TNBC, as well as the development of biomarkers and the importance of immune related adverse events (IRAEs), in this disease process.
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48
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Hossain F, Majumder S, David J, Miele L. Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions. Cancers (Basel) 2021; 13:cancers13153739. [PMID: 34359640 PMCID: PMC8345034 DOI: 10.3390/cancers13153739] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/10/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The implementation of precision medicine will revolutionize cancer treatment paradigms. Notably, this goal is not far from reality: genetically similar cancers can be treated similarly. The heterogeneous nature of triple-negative breast cancer (TNBC) made it a suitable candidate to practice precision medicine. Using TNBC molecular subtyping and genomic profiling, a precision medicine-based clinical trial is ongoing. This review summarizes the current landscape and future directions of precision medicine and TNBC. Abstract Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer associated with a high recurrence and metastasis rate that affects African-American women disproportionately. The recent approval of targeted therapies for small subgroups of TNBC patients by the US ‘Food and Drug Administration’ is a promising development. The advancement of next-generation sequencing, particularly somatic exome panels, has raised hopes for more individualized treatment plans. However, the use of precision medicine for TNBC is a work in progress. This review will discuss the potential benefits and challenges of precision medicine for TNBC. A recent clinical trial designed to target TNBC patients based on their subtype-specific classification shows promise. Yet, tumor heterogeneity and sub-clonal evolution in primary and metastatic TNBC remain a challenge for oncologists to design adaptive precision medicine-based treatment plans.
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Affiliation(s)
- Fokhrul Hossain
- Department of Genetics, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA; (S.M.); (L.M.)
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA
- Correspondence:
| | - Samarpan Majumder
- Department of Genetics, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA; (S.M.); (L.M.)
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA
| | - Justin David
- School of Medicine, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA;
| | - Lucio Miele
- Department of Genetics, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA; (S.M.); (L.M.)
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA
- School of Medicine, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, LA 70112, USA;
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49
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Al-jubori AA, Sulaiman GM, Tawfeeq AT, Mohammed HA, Khan RA, Mohammed SAA. Layer-by-Layer Nanoparticles of Tamoxifen and Resveratrol for Dual Drug Delivery System and Potential Triple-Negative Breast Cancer Treatment. Pharmaceutics 2021; 13:1098. [PMID: 34371789 PMCID: PMC8309206 DOI: 10.3390/pharmaceutics13071098] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 07/07/2021] [Accepted: 07/13/2021] [Indexed: 12/27/2022] Open
Abstract
Nanoparticle development demonstrates use in various physicochemical, biological, and functional properties for biomedical applications, including anti-cancer applications. In the current study, a cancer therapeutic conjugate was produced consisting of tamoxifen (TAM) and resveratrol (RES) by layer-by-layer (LbL) nanoparticles based on lipid-based drug delivery systems and liquid crystalline nanoparticles (LCNPs) coated with multiple layers of positively charged chitosan and negatively charged hyaluronic acid for the evaluation of biocompatibility and therapeutic properties against cancer cells. Multiple techniques characterized the synthesis of TAM/RES-LbL-LCNPs, such as Fourier-transform infrared spectroscopy (FTIR), X-ray crystallography (XRD), Zeta potential analysis, particle size analysis, Field Emission Scanning Electron Microscope (FESEM), and Transmission electron microscopy (TEM). The in vitro cytotoxic effects of TAM/RES-LbL-LCNPs were investigated against human breast cancer cell line, Michigan Cancer Foundation-7 (MCF-7), and human triple-negative breast cancer cell line, Centre Antoine Lacassagne-51 (CAL-51), using various parameters. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay confirmed that the treatment of cells with TAM/RES-LbL-LCNPs caused a reduction in cell proliferation, and no such inhibition was observed with human normal liver cell line: American Type Culture Collection Cell Line-48 (WRL-68 [ATCC CL-48]). Fluorescent microscopy examined the ability of Fluorescein isothiocyanate (FITC) to bind to TAM/RES-LbL-LCNPs along with their cellular uptake. Apoptosis determination was performed using hematoxylin-eosin and acridine orange-propidium iodide double staining. The expression of P53 and caspase-8 was analyzed by flow cytometry analysis. An in vivo study determined the toxicity of TAM/RES-LbL-LCNPs in mice and assessed the functional marker changes in the liver and kidneys. No significant statistical differences were found for the tested indicators. TAM/RES-LbL-LCNP treatment showed no apparent damages or histopathological abnormalities in the heart, lung, liver, spleen, and kidney histological images. The current findings observed for the first time propose that TAM/RES-LbL-LCNPs provide a new and safer method to use phytochemicals in combinatorial therapy and provide a novel treatment approach against breast cancers.
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Affiliation(s)
- Ali A. Al-jubori
- Division of Biotechnology, Department of Applied Sciences, University of Technology, Baghdad 10066, Iraq; (A.A.A.-j.); (G.M.S.)
| | - Ghassan M. Sulaiman
- Division of Biotechnology, Department of Applied Sciences, University of Technology, Baghdad 10066, Iraq; (A.A.A.-j.); (G.M.S.)
| | - Amer T. Tawfeeq
- Molecular Biology Department, Iraqi Center for Cancer and Medical Genetics Research, Mustansiriyah University, Baghdad 10052, Iraq;
| | - Hamdoon A. Mohammed
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia; (H.A.M.); (R.A.K.)
- Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Cairo 11371, Egypt
| | - Riaz A. Khan
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia; (H.A.M.); (R.A.K.)
| | - Salman A. A. Mohammed
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
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50
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Vito A, Salem O, El-Sayes N, MacFawn IP, Portillo AL, Milne K, Harrington D, Ashkar AA, Wan Y, Workenhe ST, Nelson BH, Bruno TC, Mossman KL. Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells. Commun Biol 2021; 4:859. [PMID: 34253827 PMCID: PMC8275624 DOI: 10.1038/s42003-021-02375-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022] Open
Abstract
Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade. Whole-tumor RNA sequencing of mice treated with FEC + oHSV-1 shows an upregulation of B cell receptor signaling pathways and depletion of B cells prior to the start of treatment in mice results in complete loss of therapeutic efficacy and expansion of myeloid-derived suppressor cells. Additionally, RNA sequencing data shows that FEC + oHSV-1 suppresses genes associated with myeloid-derived suppressor cells, a key population of cells that drive immune escape and mediate therapeutic resistance. These findings highlight the importance of tumor-infiltrating B cells as drivers of antitumor immunity and their potential role in the regulation of myeloid-derived suppressor cells.
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Affiliation(s)
- Alyssa Vito
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Omar Salem
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Nader El-Sayes
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Ian P MacFawn
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Ana L Portillo
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Katy Milne
- Deeley Research Centre, BC Cancer, Victoria, BC, Canada
| | | | - Ali A Ashkar
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Yonghong Wan
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Samuel T Workenhe
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Brad H Nelson
- Deeley Research Centre, BC Cancer, Victoria, BC, Canada
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Tullia C Bruno
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Karen L Mossman
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
- Department of Medicine, McMaster University, Hamilton, ON, Canada.
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