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Yang Y, Wang Y, Jin X, He W. Single-cell RNA-sequencing reveals cellular heterogeneity and immune microenvironment characteristics between ocular adnexal mucosa-associated lymphoid lymphoma and IgG4-related ophthalmic disease. Front Immunol 2025; 16:1508559. [PMID: 40078987 PMCID: PMC11897659 DOI: 10.3389/fimmu.2025.1508559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/22/2025] [Indexed: 03/14/2025] Open
Abstract
Introduction The molecular pathogenesis of ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma and IgG4-related ophthalmic disease (IgG4-ROD) remains incompletely understood. Differentiating between the two diseases is vital given that the diagnostic evaluation and treatment approaches can vary significantly; this difficulty in distinction is exacerbated by the absence of specific biomarkers. This study aimed to investigate the differences between these two diseases based on their cellular composition, transcriptional heterogeneity, and the immune microenvironment using single-cell RNA transcriptional sequencing (scRNA-seq) technology. Methods We collected orbital lacrimal gland region tissue samples from three patients with MALT lymphoma and another three with IgG4-ROD and performed single-cell sequencing experiments. Subsequently, we conducted bioinformatics analyses, including cell subpopulation segmentation and inter-group comparison, tumor cell identification, functional enrichment analysis, and pseudotime trajectory analysis. Furthermore, we analyzed the cellular communication between tumor B-cell and T-cell subsets within the immune microenvironment of MALT lymphoma tissues. We performed immunofluorescence assays to verify the co-expression of receptor-ligand pairs. Results A total of six major cell subpopulations were identified, with B-cells and T-cells being the predominant cell types. All B-cell subpopulations in MALT lymphomas are malignant, exhibiting significant intratumoral and intertumoral heterogeneity. Reclustering of the T-cell subpopulation identified five major T-cell subpopulations. Pseudotime analysis revealed that CD4+ naive T-cells in MALT lymphoma patients were highly likely to differentiate into follicular helper T-cells, whereas, in IgG4-ROD patients, CD4+ naive T-cells were highly likely to differentiate into regulatory T-cells. Intercellular communication analysis revealed that the CD27-CD70 immune checkpoint receptor-ligand pair and CXCL13-CXCR5 chemokine receptor-ligand pair were significantly upregulated between malignant B-cells and T-cells subpopulations. Conclusion This study is the first to conduct a comparative single-cell transcriptome sequencing analysis of ocular adnexal MALT lymphoma and IgG4-ROD. Our results reveal the cellular composition, key pathways, and critical immune microenvironment implicated in the development of these two diseases. These findings provide important insights into the pathogenesis of these two diseases and highlight the differences between them.
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Affiliation(s)
- Yu Yang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Ophthalmology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yujiao Wang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xuelian Jin
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Weimin He
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Martello SE, Xia J, Kusunose J, Hacker BC, Mayeaux MA, Lin EJ, Hawkes A, Singh A, Caskey CF, Rafat M. Ultrafast power doppler ultrasound enables longitudinal tracking of vascular changes that correlate with immune response after radiotherapy. Theranostics 2024; 14:6883-6896. [PMID: 39629131 PMCID: PMC11610147 DOI: 10.7150/thno.97759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 10/09/2024] [Indexed: 12/06/2024] Open
Abstract
Rationale: While immunotherapy shows great promise in patients with triple negative breast cancer, many will not respond to treatment. Radiotherapy has the potential to prime the tumor-immune microenvironment for immunotherapy. However, predicting response is difficult due to tumor heterogeneity across patients, which necessitates personalized medicine strategies that incorporate tumor tracking into the therapeutic approach. Here, we investigated the use of ultrasound (US) imaging of the tumor vasculature to monitor the tumor response to treatment. Methods: We utilized ultrafast power doppler US to track the vascular response to radiotherapy over time. We used 4T1 (metastatic) and 67NR (non-metastatic) breast cancer models to determine if US measurements corroborate conventional immunostaining analysis of the tumor vasculature. To evaluate the effects of radiation, tumor volume and vascular index were calculated using US, and the correlation between vascular changes and immune cell infiltration was determined. Results: US tumor measurements and the quantified vascular response to radiation were confirmed with caliper measurements and immunostaining, respectively, demonstrating a proof-of-principle method for non-invasive vascular monitoring. Additionally, we found significant infiltration of CD8+ T cells into irradiated tumors 10 days after radiation, which followed a sustained decline in vascular index and an increase in splenic CD8+ T cells that was first observed 1 day post-radiation. Conclusions: Our findings reveal that ultrafast power doppler US can evaluate changes in tumor vasculature that are indicative of shifts in the tumor-immune microenvironment. This work may lead to improved patient outcomes through observing and predicting response to therapy.
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Affiliation(s)
- Shannon E. Martello
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA
| | - Jixin Xia
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Jiro Kusunose
- Department of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Benjamin C. Hacker
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA
| | - McKenzie A. Mayeaux
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Erica J. Lin
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Adrienne Hawkes
- Department of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Aparna Singh
- Department of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Charles F. Caskey
- Department of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Marjan Rafat
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
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Martello SE, Xia J, Kusunose J, Hacker BC, Mayeaux MA, Lin EJ, Hawkes A, Singh A, Caskey CF, Rafat M. Ultrafast Power Doppler Ultrasound Enables Longitudinal Tracking of Vascular Changes that Correlate with Immune Response After Radiotherapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.08.04.552076. [PMID: 37577718 PMCID: PMC10418282 DOI: 10.1101/2023.08.04.552076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Background While immunotherapy shows great promise in patients with triple negative breast cancer, many will not respond to treatment. Radiotherapy has the potential to prime the tumor-immune microenvironment for immunotherapy. However, predicting response is difficult due to tumor heterogeneity across patients, which necessitates personalized medicine strategies that incorporate tumor tracking into the therapeutic approach. Here, we investigated the use of ultrasound (US) imaging of the tumor vasculature to monitor the tumor response to treatment. Methods We utilized ultrafast power doppler US to track the vascular response to radiotherapy over time. We used 4T1 (metastatic) and 67NR (non-metastatic) breast cancer models to determine if US measurements corroborate conventional immunostaining analysis of the tumor vasculature. To evaluate the effects of radiation, tumor volume and vascular index were calculated using US, and the correlation between vascular changes and immune cell infiltration was determined. Results US tumor measurements and the quantified vascular response to radiation were confirmed with caliper measurements and immunostaining, respectively, demonstrating a proof-of-principle method for non-invasive vascular monitoring. Additionally, we found significant infiltration of CD8 + T cells into irradiated tumors 10 days after radiation, which followed a sustained decline in vascular index and an increase in splenic CD8 + T cells that was first observed 1 day post-radiation. Conclusions Our findings reveal that ultrafast power doppler US can evaluate changes in tumor vasculature that are indicative of shifts in the tumor-immune microenvironment. This work may lead to improved patient outcomes through observing and predicting response to therapy.
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diZerega GS, Maulhardt HA, Verco SJ, Marin AM, Baltezor MJ, Mauro SA, Iacobucci MA. Intratumoral Injection of Large Surface Area Microparticle Taxanes in Carcinomas Increases Immune Effector Cell Concentrations, Checkpoint Expression, and Synergy with Checkpoint Inhibitors: A Review of Preclinical and Clinical Studies. Oncol Ther 2024; 12:31-55. [PMID: 38289576 PMCID: PMC10881942 DOI: 10.1007/s40487-024-00261-y] [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: 11/03/2023] [Accepted: 01/04/2024] [Indexed: 02/23/2024] Open
Abstract
This review summarizes development of large surface area microparticle paclitaxel (LSAM-PTX) and docetaxel (LSAM-DTX) for local treatment of primary carcinomas with emphasis on immunomodulation. Intratumoral (IT) delivery of LSAM-PTX and LSAM-DTX provides continuous, therapeutic drug levels for several weeks. Preclinical studies and clinical trials reported a reduction in tumor volume (TV) and immunomodulation in primary tumor and peripheral blood with increases in innate and adaptive immune cells and decreases in suppressor cells. Increased levels of checkpoint expression of immune cells occurred in clinical trials of high-risk non-muscle-invasive bladder cancer (LSAM-DTX) and unresectable localized pancreatic cancer (LSAM-PTX). TV reduction and increases in immune effector cells occurred following IT LSAM-DTX and IT LSAM-PTX together with anti-mCTLA-4 and anti-mPD-1, respectively. Synergistic benefits from combinatorial therapy in a 4T1-Luc breast cancer model included reduction of metastasis with IT LSAM-DTX + anti-mCTLA-4. IT LSAM-PTX and LSAM-DTX are tumoricidal, immune enhancing, and may improve solid tumor response to immune checkpoint inhibitors without additional systemic toxicity.
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Affiliation(s)
- Gere S diZerega
- US Biotest, Inc., 231 Bonetti Drive, Suite 240, San Luis Obispo, CA, 93401, USA.
- NanOlogy, LLC., 3909 Hulen Street, Fort Worth, TX, 76107, USA.
| | - Holly A Maulhardt
- US Biotest, Inc., 231 Bonetti Drive, Suite 240, San Luis Obispo, CA, 93401, USA
| | - Shelagh J Verco
- US Biotest, Inc., 231 Bonetti Drive, Suite 240, San Luis Obispo, CA, 93401, USA
| | - Alyson M Marin
- US Biotest, Inc., 231 Bonetti Drive, Suite 240, San Luis Obispo, CA, 93401, USA
| | | | - Samantha A Mauro
- US Biotest, Inc., 231 Bonetti Drive, Suite 240, San Luis Obispo, CA, 93401, USA
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Abaza A, Sid Idris F, Anis Shaikh H, Vahora I, Moparthi KP, Al Rushaidi MT, Muddam MR, Obajeun OA, Jaramillo AP, Khan S. Programmed Cell Death Protein 1 (PD-1) and Programmed Cell Death Ligand 1 (PD-L1) Immunotherapy: A Promising Breakthrough in Cancer Therapeutics. Cureus 2023; 15:e44582. [PMID: 37667784 PMCID: PMC10475160 DOI: 10.7759/cureus.44582] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 09/02/2023] [Indexed: 09/06/2023] Open
Abstract
The advent of immune checkpoint inhibitors has revolutionized cancer therapy by leveraging the body's immune system to combat malignancies effectively. Among these groundbreaking agents, programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have emerged as pivotal therapeutic approaches. PD-L1, a key protein expressed on the surface of various cells, including cancer cells, plays a central role in immune regulation by interacting with the programmed cell death protein 1 (PD-1) receptor on T-cells leading to immune suppression. The substantial increase in PD-L1 expression on cancer cell surfaces has driven the exploration of PD-1/PD-L1 inhibitors as potential immunotherapeutic agents. These inhibitors are monoclonal antibodies designed to impede the PD-L1 and PD-1 interaction and disrupt the immunosuppressive signal, thereby reinvigorating the anti-tumor immune response mediated by activated T-cells. Clinical trials investigating PD-1/PD-L1 inhibitors have demonstrated remarkable efficacy in the treatment of diverse advanced or metastatic cancers, including leukemia, non-small cell lung (NSCLC), hepatocellular, melanoma, gastric, colorectal, and breast cancers, among others. Regulatory approvals have been granted for both monotherapy and combination therapy with other cancer treatments, encompassing chemotherapy and additional immune checkpoint inhibitors. While PD-1/PD-L1 inhibitors have exhibited significant success, they are not devoid of challenges. The emergence of intrinsic or acquired resistance, as well as immune-related adverse events, warrants thorough investigation and management. Consequently, researchers have embarked on combination trials to augment the therapeutic potential of PD-1/PD-L1 inhibitors and surmount resistance mechanisms.
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Affiliation(s)
- Abdelrahman Abaza
- Pathology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Faten Sid Idris
- Pediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Humna Anis Shaikh
- Pediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ilma Vahora
- General Surgery, Saint George's University School of Medicine, Chicago, USA
| | - Kiran Prasad Moparthi
- College of Medicine, Sri Venkata Sai (SVS) Medical College, Mahabubnagar, IND
- General Practice, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Majdah T Al Rushaidi
- Psychology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Meghana Reddy Muddam
- General Practice, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
- College of Medicine, Sri Venkata Sai (SVS) Medical College, Mahabubnagar, IND
| | - Omobolanle A Obajeun
- Paediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Safeera Khan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Hadžikadić-Gušić L, Cerić T, Marijanović I, Iljazović E, Koprić D, Zorlak A, Tanović M, Mekić-Abazović A, Šišić I, Delić U, Mustedanagić-Mujanović J, Aginčić A, Bećiragić E, L Greene F. Guidelines for breast cancer management in Bosnia and Herzegovina. BIOMOLECULES AND BIOMEDICINE 2023; 23:2-14. [PMID: 35880400 PMCID: PMC9901905 DOI: 10.17305/bjbms.2022.7504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/12/2022] [Indexed: 02/08/2023]
Abstract
Breast cancer is the most common cancer among women. In Bosnia and Herzegovina, accurate data on the status of breast cancer are lacking due to the absence of a central registry. Multiple international guidelines imply that institutions that monitor breast cancer patients should have optimal therapeutic options for treatment. In addition, there have been several international consensus guidelines written on the management of breast cancer. Application of consensus guidelines has previously been demonstrated to have a positive influence on breast cancer care. The importance of specialty breast centers has previously been reported. As part of the 2021 Bosnian-Herzegovinian American Academy of Arts and Sciences (BHAAAS) conference in Mostar, a round table of multidisciplinary specialists from Bosnia and Herzegovina and the diaspora was held. All were either members of BHAAAS or regularly participate in collaborative projects. The focus of the consortium was to write the first multidisciplinary guidelines for the general management of breast cancer in Bosnia and Herzegovina. Guidelines were developed for each area of breast cancer treatment and management. These guidelines will serve as a resource for practitioners managing breast cancer in the Bosnia and Herzegovina region. This might also be of benefit to the ministry of health and any future investors interested in developing breast cancer care policies in this region of the world.
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Affiliation(s)
- Lejla Hadžikadić-Gušić
- Department of Surgical Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA,Correspondence to Lejla Hadžikadić-Gušić:
| | - Timur Cerić
- Department of Medical Oncology, University Clinical Center, Sarajevo, Bosnia and Herzegovina
| | - Inga Marijanović
- Clinic of Oncology, University Clinical Hospital, Mostar, Bosnia and Herzegovina
| | - Ermina Iljazović
- Department of Pathology, University Clinical Center, Tuzla, Bosnia and Herzegovina
| | - Dijana Koprić
- Department of Medical Oncology and Radiation Oncology, University Clinical Center, Tuzla, Bosnia and Herzegovina
| | - Anela Zorlak
- Genetics Counseling, Genetika, Sarajevo, Bosnia and Herzegovina
| | - Mahira Tanović
- Plastic and Reconstructive Surgery, Advanced Plastic Surgery of North Shore, NY, USA
| | - Alma Mekić-Abazović
- Department of Medical Oncology, Kanton Hospital Zenica, Zenica, Bosnia and Herzegovina
| | - Ibrahim Šišić
- Department of Medical Oncology, Kanton Hospital Zenica, Zenica, Bosnia and Herzegovina
| | - Una Delić
- Department of Radiology, University Clinical Center, Sarajevo, Bosnia and Herzegovina
| | | | - Alija Aginčić
- Plastic and Reconstructive Surgery, Center for Aesthetic Surgery, Nasa Mala Klinika (Our Little Clinic), Sarajevo, Bosnia and Heregovina
| | - Edin Bećiragić
- Department of Surgery, Dr. Abdulah Nakas General Hospital, Sarajevo, Bosnia and Herzegovina
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Jungles KM, Holcomb EA, Pearson AN, Jungles KR, Bishop CR, Pierce LJ, Green MD, Speers CW. Updates in combined approaches of radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Front Oncol 2022; 12:1022542. [PMID: 36387071 PMCID: PMC9643771 DOI: 10.3389/fonc.2022.1022542] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/27/2022] [Indexed: 12/05/2022] Open
Abstract
Breast cancer is the most prevalent non-skin cancer diagnosed in females and developing novel therapeutic strategies to improve patient outcomes is crucial. The immune system plays an integral role in the body’s response to breast cancer and modulating this immune response through immunotherapy is a promising therapeutic option. Although immune checkpoint inhibitors were recently approved for the treatment of breast cancer patients, not all patients respond to immune checkpoint inhibitors as a monotherapy, highlighting the need to better understand the biology underlying patient response. Additionally, as radiotherapy is a critical component of breast cancer treatment, understanding the interplay of radiation and immune checkpoint inhibitors will be vital as recent studies suggest that combined therapies may induce synergistic effects in preclinical models of breast cancer. This review will discuss the mechanisms supporting combined approaches with radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Moreover, this review will analyze the current clinical trials examining combined approaches of radiotherapy, immunotherapy, chemotherapy, and targeted therapy. Finally, this review will evaluate data regarding treatment tolerance and potential biomarkers for these emerging therapies aimed at improving breast cancer outcomes.
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Affiliation(s)
- Kassidy M. Jungles
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, United States
| | - Erin A. Holcomb
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Ashley N. Pearson
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Kalli R. Jungles
- Department of Biology, Saint Mary’s College, Notre Dame, IN, United States
| | - Caroline R. Bishop
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
| | - Lori J. Pierce
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
| | - Michael D. Green
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States
- Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, United States
- *Correspondence: Michael D. Green, ; Corey W. Speers,
| | - Corey W. Speers
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Radiation Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Case Comprehensive Cancer Center, Cleveland, OH, United States
- *Correspondence: Michael D. Green, ; Corey W. Speers,
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Dobrovolskaia MA. Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory. Front Immunol 2022; 13:984252. [PMID: 36304452 PMCID: PMC9592561 DOI: 10.3389/fimmu.2022.984252] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Nanotechnology carriers have become common in pharmaceutical products because of their benefits to drug delivery, including reduced toxicities and improved efficacy of active pharmaceutical ingredients due to targeted delivery, prolonged circulation time, and controlled payload release. While available examples of reduced drug toxicity through formulation using a nanocarrier are encouraging, current data also demonstrate that nanoparticles may change a drug’s biodistribution and alter its toxicity profile. Moreover, individual components of nanoparticles and excipients commonly used in formulations are often not immunologically inert and contribute to the overall immune responses to nanotechnology-formulated products. Said immune responses may be beneficial or adverse depending on the indication, dose, dose regimen, and route of administration. Therefore, comprehensive toxicology studies are of paramount importance even when previously known drugs, components, and excipients are used in nanoformulations. Recent data also suggest that, despite decades of research directed at hiding nanocarriers from the immune recognition, the immune system’s inherent property of clearing particulate materials can be leveraged to improve the therapeutic efficacy of drugs formulated using nanoparticles. Herein, I review current knowledge about nanoparticles’ interaction with the immune system and how these interactions contribute to nanotechnology-formulated drug products’ safety and efficacy through the lens of over a decade of nanoparticle characterization at the Nanotechnology Characterization Laboratory.
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Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, Wu W, Han L, Wang S. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol 2022; 13:964442. [PMID: 36177034 PMCID: PMC9513184 DOI: 10.3389/fimmu.2022.964442] [Citation(s) in RCA: 232] [Impact Index Per Article: 77.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Programmed cell death protein-1 (PD-1) is a checkpoint receptor expressed on the surface of various immune cells. PD-L1, the natural receptor for PD-1, is mainly expressed in tumor cells. Studies have indicated that PD-1 and PD-L1 are closely associated with the progression of human cancers and are promising biomarkers for cancer therapy. Moreover, the interaction of PD-1 and PD-L1 is one of the important mechanism by which human tumors generate immune escape. This article provides a review on the role of PD-L1/PD-1, mechanisms of immune response and resistance, as well as immune-related adverse events in the treatment of anti-PD-1/PD-L1 immunotherapy in human cancers. Moreover, we summarized a large number of clinical trials to successfully reveal that PD-1/PD-L1 Immune-checkpoint inhibitors have manifested promising therapeutic effects, which have been evaluated from different perspectives, including overall survival, objective effective rate and medium progression-free survival. Finally, we pointed out the current problems faced by PD-1/PD-L1 Immune-checkpoint inhibitors and its future prospects. Although PD-1/PD-L1 immune checkpoint inhibitors have been widely used in the treatment of human cancers, tough challenges still remain. Combination therapy and predictive models based on integrated biomarker determination theory may be the future directions for the application of PD-1/PD-L1 Immune-checkpoint inhibitors in treating human cancers.
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Affiliation(s)
- Qing Tang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yun Chen
- Department of Organ Transplantation, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaojuan Li
- Institute of Rehabilitation Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shunqin Long
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yao Shi
- Department of Cerebrovascular Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yaya Yu
- Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Wanyin Wu
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Ling Han
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Sumei Wang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
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Montella M, Sabetta R, Ronchi A, De Sio M, Arcaniolo D, De Vita F, Tirino G, Caputo A, D'Antonio A, Fiorentino F, Facchini G, Lauro GD, Perdonà S, Ventriglia J, Aquino G, Feroce F, Borges Dos Reis R, Neder L, Brunelli M, Franco R, Zito Marino F. Immunotherapy in Penile Squamous Cell Carcinoma: Present or Future? Multi-Target Analysis of Programmed Cell Death Ligand 1 Expression and Microsatellite Instability. Front Med (Lausanne) 2022; 9:874213. [PMID: 35592855 PMCID: PMC9113025 DOI: 10.3389/fmed.2022.874213] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/04/2022] [Indexed: 11/13/2022] Open
Abstract
Background Penile cancer (PC) is an extremely rare malignancy, and the patients at advanced stages have currently limited treatment options with disappointing results. Immune checkpoint inhibitors anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are currently changing the treatment of several tumors. Furthermore, the microsatellite instability (MSI) and the deficient mismatch repair system (dMMR) proteins represent predictive biomarkers for response to immune checkpoint therapy. Until present, few data have been reported related to PD-L1 expression and MSI in PC. The main aim of our study was the evaluation of PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) in immune cells and the analysis of dMMR/MSI status in a large series of PCs. Methods A series of 72 PC, including 65 usual squamous cell carcinoma (USCC), 1 verrucous, 4 basaloid, 1 warty, and 1 mixed (warty-basaloid), was collected. Immunohistochemistry (IHC) was performed to assess PD-L1 expression using two different anti-PD-L1 antibodies (clone SP263 and SP142 Ventana) and MMR proteins expression using anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6 antibodies. PCR analysis was performed for the detection of MSI status. Results Of the 72 PC cases analyzed by IHC, 45 (62.5%) cases were TC positive and 57 (79%) cases were combined positive score (CPS) using PDL1 SP263. In our cohort, TILs were present in 62 out of 72 cases (86.1%), 47 (75.8%) out of 62 cases showed positivity to PDL1 clone SP142. In our series, 59 cases (82%) had pMMR, 12 cases (16.7%) had lo-paMMR, and only 1 case (1.3%) had MMR. PCR results showed that only one case lo-paMMR was MSI-H, and the case dMMR by IHC not confirmed MSI status. Conclusion Our findings showed that PD-L1 expression and MSI status represent frequent biological events in this tumor suggesting a rationale for a new frontier in the treatment of patients with PC based on the immune checkpoint inhibitors.
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Affiliation(s)
- Marco Montella
- Pathology Unit, Department of Mental Health, Physic and Preventive Medicine University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Rosalaura Sabetta
- Pathology Unit, Department of Mental Health, Physic and Preventive Medicine University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Andrea Ronchi
- Pathology Unit, Department of Mental Health, Physic and Preventive Medicine University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marco De Sio
- Urology Unit, Department of Woman Child and of General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Davide Arcaniolo
- Urology Unit, Department of Woman Child and of General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Ferdinando De Vita
- Oncology Unit, Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Tirino
- Oncology Unit, Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Alessandro Caputo
- Department of Medicine and Surgery, University Hospital "San Giovanni di Dio e Ruggi D'Aragona", University of Salerno, Salerno, Italy
| | - Antonio D'Antonio
- Department of Pathology, University Hospital "San Giovanni di Dio e Ruggi D'Aragona", Salerno, Italy
| | | | - Gaetano Facchini
- Medical Oncology Unit, S.M. delle Grazie Hospital, Pozzuoli, Italy
| | | | - Sisto Perdonà
- Department of Urogynecology, National Cancer Institute, Pascale Foundation (Scientific Institute for Research and Healthcare), Naples, Italy
| | - Jole Ventriglia
- Department of Urogynecology, National Cancer Institute, Pascale Foundation (Scientific Institute for Research and Healthcare), Naples, Italy
| | - Gabriella Aquino
- Pathology Unit, Istituto Nazionale Tumori Fondazione G. Pascale IRCCS, Naples, Italy
| | - Florinda Feroce
- Pathology Unit, Istituto Nazionale Tumori Fondazione G. Pascale IRCCS, Naples, Italy
| | - Rodolfo Borges Dos Reis
- Urology Division, Department of Surgery and Anatomy, Ribeirão Preto School Medicine, University of São Paulo, Ribeirão Preto, Brazil
| | - Luciano Neder
- Department of Pathology and Forensic Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Matteo Brunelli
- Department of Pathology, University of Verona, Verona, Italy
| | - Renato Franco
- Pathology Unit, Department of Mental Health, Physic and Preventive Medicine University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Federica Zito Marino
- Pathology Unit, Department of Mental Health, Physic and Preventive Medicine University of Campania "Luigi Vanvitelli", Naples, Italy
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11
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Duan S, Buxton ILO. Evolution of Medical Approaches and Prominent Therapies in Breast Cancer. Cancers (Basel) 2022; 14:2450. [PMID: 35626053 PMCID: PMC9140094 DOI: 10.3390/cancers14102450] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 12/10/2022] Open
Abstract
An examination of the origins of medical approaches to breast cancer marks this disease as one of the most difficult to manage. As the early identification, diagnosis and treatment of breast cancer evolve, we will move to a time when each patient and their cancer can be assessed to determine unique patient-specific (personalized) approaches to therapy. Humans have attempted to manage breast cancer for millennia. Even today, the disease claims thousands of lives each year. In light of the increasingly sophisticated understanding of cancer diagnosis and treatment, together with our ultimate failure to offer a cure in the most difficult cases, it is instructive to reflect on the beginnings of our understanding.
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Affiliation(s)
- Suzann Duan
- Department of Pharmacology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA;
| | - Iain L. O. Buxton
- Department of Medicine, University of Arizona College of Medicine, Tucson, AZ 85724, USA
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12
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Jabbarzadeh Kaboli P, Shabani S, Sharma S, Partovi Nasr M, Yamaguchi H, Hung MC. Shedding light on triple-negative breast cancer with Trop2-targeted antibody-drug conjugates. Am J Cancer Res 2022; 12:1671-1685. [PMID: 35530278 PMCID: PMC9077081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 04/02/2022] [Indexed: 06/14/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is well-known as the most aggressive subtype of breast cancer. Because TNBC does not express Her2, estrogen receptor, and progesterone receptors, there had been no effective U.S. Food and Drug Administration-approved targeted therapy for it until PARP inhibitors and two PD-1/PD-L1 monoclonal antibodies were approved for treatment of TNBC. Most recently, an antibody-drug conjugate (ADC), called sacituzumab govitecan (SG), was approved for the treatment of TNBC patients previously received chemotherapy with advanced disease. SG consists of an anti-trophoblast cell-surface antigen 2 (Trop2) antibody conjugated with a topoisomerase I inhibitor, SN-38, which is diffused out of the targeted Trop2 positive cancer cells and induces the bystander killing effect on surrounding cells regardless of their Trop2 expression status. In the Phase III clinical trial, TNBC patients treated with SG showed significantly longer progression-free and overall survival compared to those who were received chemotherapy. In the present review, we summarized the cellular function and signaling of Trop2, the mechanism of action of SG, and the clinical trials of SG that led to its quick approval for TNBC. In addition, we introduced the current ongoing clinical trials of SG as well as another Trop2 ADC, which has potential to overcome some disadvantages of SG.
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Affiliation(s)
- Parham Jabbarzadeh Kaboli
- Graduate Institute of Biomedical Sciences, China Medical UniversityTaichung, Taiwan
- Center for Molecular Medicine, China Medical University HospitalTaichung 40402, Taiwan
- Research Center for Cancer Biology, China Medical UniversityTaichung 40402, Taiwan
| | - Shima Shabani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares UniversityP.O. Box 14115/111, Tehran, Iran
| | - Sagar Sharma
- Institute of Biology, Biotechnology, and Environmental Protection, Faculty of Natural Sciences, University of Silesia in Katowice40-032 Katowice, Poland
| | - Minoo Partovi Nasr
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB)Tehran, Iran
| | - Hirohito Yamaguchi
- Graduate Institute of Biomedical Sciences, China Medical UniversityTaichung, Taiwan
- Center for Molecular Medicine, China Medical University HospitalTaichung 40402, Taiwan
- Research Center for Cancer Biology, China Medical UniversityTaichung 40402, Taiwan
| | - Mien-Chie Hung
- Graduate Institute of Biomedical Sciences, China Medical UniversityTaichung, Taiwan
- Center for Molecular Medicine, China Medical University HospitalTaichung 40402, Taiwan
- Research Center for Cancer Biology, China Medical UniversityTaichung 40402, Taiwan
- Department of Biotechnology, Asia UniversityTaichung 41354, Taiwan
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13
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Valencia GA, Rioja P, Morante Z, Ruiz R, Fuentes H, Castaneda CA, Vidaurre T, Neciosup S, Gomez HL. Immunotherapy in triple-negative breast cancer: A literature review and new advances. World J Clin Oncol 2022; 13:219-236. [PMID: 35433291 PMCID: PMC8966508 DOI: 10.5306/wjco.v13.i3.219] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 11/23/2021] [Accepted: 02/19/2022] [Indexed: 02/06/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly complex, heterogeneous disease and historically has limited treatment options. It has a high probability of disease recurrence and rapid disease progression despite adequate systemic treatment. Immunotherapy has emerged as an important alternative in the management of this malignancy, showing an impact on progression-free survival and overall survival in selected populations. In this review we focused on immunotherapy and its current relevance in the management of TNBC, including various scenarios (metastatic and early -neoadjuvant, adjuvant-), new advances in this subtype and the research of potential predictive biomarkers of response to treatment.
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Affiliation(s)
| | - Patricia Rioja
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Zaida Morante
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Rossana Ruiz
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Hugo Fuentes
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Carlos A Castaneda
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Tatiana Vidaurre
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Silvia Neciosup
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
| | - Henry L Gomez
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15036, Peru
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14
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Napier TS, Hunter CL, Song PN, Larimer BM, Sorace AG. Preclinical PET Imaging of Granzyme B Shows Promotion of Immunological Response Following Combination Paclitaxel and Immune Checkpoint Inhibition in Triple Negative Breast Cancer. Pharmaceutics 2022; 14:pharmaceutics14020440. [PMID: 35214172 PMCID: PMC8875418 DOI: 10.3390/pharmaceutics14020440] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 12/18/2022] Open
Abstract
Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to IMT with chemotherapy in TNBC. TNBC mouse models received the paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 (anti-PD1) and anti-cytotoxic T-lymphocyte 4 (anti-CTLA4). GZP-PET imaging was performed on treatment days 0, 3, and 6. Mean standard uptake value (SUVmean), effector cell fractions, and SUV histograms were compared. Mice were sacrificed at early imaging timepoints for cytokine and histological analyses. GZP-PET imaging data revealed differences prior to tumor volume changes. By day six, responders had SUVmean ≥ 2.2-fold higher (p < 0.0037) and effector cell fractions ≥ 1.9-fold higher (p = 0.03) compared to non-responders. IMT/PTX resulted in a significantly different SUV distribution compared to control, indicating broader distribution of activated intratumoral T-cells. IMT/PTX resulted in significantly more necrotic tumor tissue and increased levels of IL-2, 4, and 12 compared to control. Results implicate immunogenic cell death through upregulation of key Th1/Th2 cytokines by IMT/PTX. Noninvasive PET imaging can provide data on the TNBC tumor microenvironment, specifically intratumoral effector cell activation, predicting response to IMT plus chemotherapy.
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Affiliation(s)
- Tiara S. Napier
- Graduate Biomedical Sciences Cancer Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.S.N.); (C.L.H.); (P.N.S.)
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Chanelle L. Hunter
- Graduate Biomedical Sciences Cancer Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.S.N.); (C.L.H.); (P.N.S.)
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Patrick N. Song
- Graduate Biomedical Sciences Cancer Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.S.N.); (C.L.H.); (P.N.S.)
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Benjamin M. Larimer
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Anna G. Sorace
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: ; Tel.: +1-(205)-934-3116, Fax: +1-(205)-975-6522
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15
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Xuan DTM, Wu CC, Kao TJ, Ta HDK, Anuraga G, Andriani V, Athoillah M, Chiao CC, Wu YF, Lee KH, Wang CY, Chuang JY. Prognostic and immune infiltration signatures of proteasome 26S subunit, non-ATPase (PSMD) family genes in breast cancer patients. Aging (Albany NY) 2021; 13:24882-24913. [PMID: 34839279 PMCID: PMC8660617 DOI: 10.18632/aging.203722] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/27/2021] [Indexed: 12/24/2022]
Abstract
The complexity of breast cancer includes many interacting biological processes that make it difficult to find appropriate therapeutic treatments. Therefore, identifying potential diagnostic and prognostic biomarkers is urgently needed. Previous studies demonstrated that 26S proteasome delta subunit, non-ATPase (PSMD) family members significantly contribute to the degradation of damaged, misfolded, abnormal, and foreign proteins. However, transcriptional expressions of PSMD family genes in breast cancer still remain largely unexplored. Consequently, we used a holistic bioinformatics approach to explore PSMD genes involved in breast cancer patients by integrating several high-throughput databases, including The Cancer Genome Atlas (TCGA), cBioPortal, Oncomine, and Kaplan-Meier plotter. These data demonstrated that PSMD1, PSMD2, PSMD3, PSMD7, PSMD10, PSMD12, and PSMD14 were expressed at significantly higher levels in breast cancer tissue compared to normal tissues. Notably, the increased expressions of PSMD family genes were correlated with poor prognoses of breast cancer patients, which suggests their roles in tumorigenesis. Meanwhile, network and pathway analyses also indicated that PSMD family genes were positively correlated with ubiquinone metabolism, immune system, and cell-cycle regulatory pathways. Collectively, this study revealed that PSMD family members are potential prognostic biomarkers for breast cancer progression and possible promising clinical therapeutic targets.
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Affiliation(s)
- Do Thi Minh Xuan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Chung-Che Wu
- Division of Neurosurgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.,Division of Neurosurgery, Department of Surgery, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Tzu-Jen Kao
- The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Hoang Dang Khoa Ta
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Gangga Anuraga
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.,Department of Statistics, Faculty of Science and Technology, PGRI Adi Buana University, Surabaya 60234, East Java, Indonesia
| | - Vivin Andriani
- Department of Biological Science, Faculty of Science and Technology, Universitas PGRI Adi Buana, Surabaya 60234, East Java, Indonesia
| | - Muhammad Athoillah
- Department of Statistics, Faculty of Science and Technology, PGRI Adi Buana University, Surabaya 60234, East Java, Indonesia
| | - Chung-Chieh Chiao
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Yung-Fu Wu
- Department of Medical Research, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan
| | - Kuen-Haur Lee
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.,Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chih-Yang Wang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Jian-Ying Chuang
- The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 11031, Taiwan.,Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
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16
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Chen Z, Wang M, De Wilde RL, Feng R, Su M, Torres-de la Roche LA, Shi W. A Machine Learning Model to Predict the Triple Negative Breast Cancer Immune Subtype. Front Immunol 2021; 12:749459. [PMID: 34603338 PMCID: PMC8484710 DOI: 10.3389/fimmu.2021.749459] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 08/30/2021] [Indexed: 12/29/2022] Open
Abstract
Background Immune checkpoint blockade (ICB) has been approved for the treatment of triple-negative breast cancer (TNBC), since it significantly improved the progression-free survival (PFS). However, only about 10% of TNBC patients could achieve the complete response (CR) to ICB because of the low response rate and potential adverse reactions to ICB. Methods Open datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were downloaded to perform an unsupervised clustering analysis to identify the immune subtype according to the expression profiles. The prognosis, enriched pathways, and the ICB indicators were compared between immune subtypes. Afterward, samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset were used to validate the correlation of immune subtype with prognosis. Data from patients who received ICB were selected to validate the correlation of the immune subtype with ICB response. Machine learning models were used to build a visual web server to predict the immune subtype of TNBC patients requiring ICB. Results A total of eight open datasets including 931 TNBC samples were used for the unsupervised clustering. Two novel immune subtypes (referred to as S1 and S2) were identified among TNBC patients. Compared with S2, S1 was associated with higher immune scores, higher levels of immune cells, and a better prognosis for immunotherapy. In the validation dataset, subtype 1 samples had a better prognosis than sub type 2 samples, no matter in overall survival (OS) (p = 0.00036) or relapse-free survival (RFS) (p = 0.0022). Bioinformatics analysis identified 11 hub genes (LCK, IL2RG, CD3G, STAT1, CD247, IL2RB, CD3D, IRF1, OAS2, IRF4, and IFNG) related to the immune subtype. A robust machine learning model based on random forest algorithm was established by 11 hub genes, and it performed reasonably well with area Under the Curve of the receiver operating characteristic (AUC) values = 0.76. An open and free web server based on the random forest model, named as triple-negative breast cancer immune subtype (TNBCIS), was developed and is available from https://immunotypes.shinyapps.io/TNBCIS/. Conclusion TNBC open datasets allowed us to stratify samples into distinct immunotherapy response subgroups according to gene expression profiles. Based on two novel subtypes, candidates for ICB with a higher response rate and better prognosis could be selected by using the free visual online web server that we designed.
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Affiliation(s)
- Zihao Chen
- Department of Urology, University of Freiburg, Freiburg, Germany
| | - Maoli Wang
- Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Rudy Leon De Wilde
- University Hospital for Gynecology, Pius-Hospital, University Medicine Oldenburg, Oldenburg, Germany
| | - Ruifa Feng
- Breast Center of The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Mingqiang Su
- Department of Urology, Zigong Hospital, Affiliated to Southwest Medical University, Zigong, China
| | | | - Wenjie Shi
- University Hospital for Gynecology, Pius-Hospital, University Medicine Oldenburg, Oldenburg, Germany
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17
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García-Fernández C, Saz A, Fornaguera C, Borrós S. Cancer immunotherapies revisited: state of the art of conventional treatments and next-generation nanomedicines. Cancer Gene Ther 2021; 28:935-946. [PMID: 33837365 DOI: 10.1038/s41417-021-00333-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/24/2021] [Accepted: 03/24/2021] [Indexed: 02/02/2023]
Abstract
Nowadays, the landscape of cancer treatments has broadened thanks to the clinical application of immunotherapeutics. After decades of failures, cancer immunotherapy represents an exciting alternative for those patients suffering from a wide variety of cancers, especially for those skin cancers, such as the early stages of melanoma. However, those cancers affecting internal organs still face a long way to success, because of the poor biodistribution of immunotherapies. Here, nanomedicine appears as a hopeful strategy to modulate the biodistribution aiming at target organ accumulation. In this way, efficacy will be improved, while reducing the side effects at the same time. In this review, we aim to highlight the most promising cancer immunotherapeutic strategies. From monoclonal antibodies and their traditional use as targeted therapies to their current use as immune checkpoint inhibitors; as well as adoptive cell transfer therapies; oncolytic viruses, and therapeutic cancer vaccination. Then, we aim to discuss the important role of nanomedicine to improve the performance of these immunotherapeutic tools to finally review the already marketed nanomedicine-based cancer immunotherapies.
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Affiliation(s)
- Coral García-Fernández
- Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL), Barcelona, Spain
| | - Anna Saz
- Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL), Barcelona, Spain
| | - Cristina Fornaguera
- Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL), Barcelona, Spain.
| | - Salvador Borrós
- Grup d'Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Univeritat Ramon Llull (URL), Barcelona, Spain
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18
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Nordin FJ, Pearanpan L, Chan KM, Kumolosasi E, Yong YK, Shaari K, Rajab NF. Immunomodulatory potential of Clinacanthus nutans extracts in the co-culture of triple-negative breast cancer cells, MDA-MB-231, and THP-1 macrophages. PLoS One 2021; 16:e0256012. [PMID: 34379689 PMCID: PMC8357171 DOI: 10.1371/journal.pone.0256012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 07/28/2021] [Indexed: 12/12/2022] Open
Abstract
Triple-negative breast cancer is the main type of breast carcinoma that causes mortality among women because of the limited treatment options and high recurrence. Chronic inflammation has been linked with the tumor microenvironment (TME) in breast cancer progression. Clinacanthus nutans (CN) has gained much attention because of its anticancer properties, but its mechanism remains unclear. We aimed to study the qualitative phytochemical content and elucidate the cytotoxicity effects of CN on human triple-negative breast cancer (TNBC), MDA-MB-231 and human macrophage-like cells such as THP-1 by using sulforhodamine B (SRB) assay. As highly metastatic cells, MDA-MB-231 cells can migrate to the distal position, the effect of CN on migration were also elucidated using the scratch assay. The CN effects on ameliorating chronic inflammation in TME were studied following the co-culture of MDA-MB-231/THP-1 macrophages. The cytokine expression levels of IL-6, IL-1β and tumor necrosis factor-alpha (TNF-α) were determined using ELISA assays. The results showed that both ethanolic and aqueous CN extracts contained alkaloid, phenol and tannin, flavonoid, terpenoid, glycoside and steroid. However, saponin was only found in the aqueous extract of CN. CN was not cytotoxic to both MDA-MB-231 and THP-1 cells. The ability of MDA-MB-231 to migrate was also not halted by CN treatment. However, CN ethanol extract decreased IL-6 at 25 μg/mL (p = 0.02) and 100 μg/mL (p = 0.03) but CN aqueous extract increased IL-6 expression at 50 μg/mL (p = 0.08) and 100 μg/mL (p = 0.02). IL-1β showed decreased expression after treated with CN ethanol and CN aqueous both at 25 μg/mL (p = 0.03). TNF-α were significantly decreased after CN ethanol treatment at concentration 25- (p = 0.001), 50- (p = 0.000) and 100 μg/mL (p = 0.000). CN aqueous extract slightly inhibited TNF-α at all 25–50- and 100 μg/mL (p = 0.001, p = 0.000, p = 0.000, respectively). Overall, CN acts by ameliorating the pro-inflammatory condition in the TME and may be a potential strategy for its anticancer mechanism on highly metastatic breast cancer condition. The major pathways that link both cancer and inflammation were NF-κB and STATs thus further study on the upstream and downstream pathways is needed to fully understand the mechanism of CN extracts in cooling the inflamed TME in breast cancer.
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Affiliation(s)
- Fariza Juliana Nordin
- Biomedical Science Program, Center for Healthy Aging and Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Lishantini Pearanpan
- Biomedical Science Program, Center for Healthy Aging and Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Kok Meng Chan
- Center for Toxicology and Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Endang Kumolosasi
- Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Yoke Keong Yong
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang, Seri Kembangan, Selangor, Malaysia
| | - Khozirah Shaari
- Faculty of Science, Universiti Putra Malaysia, UPM Serdang, Seri Kembangan, Malaysia
| | - Nor Fadilah Rajab
- Biomedical Science Program, Center for Healthy Aging and Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
- * E-mail:
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19
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Kothari C, Clemenceau A, Ouellette G, Ennour-Idrissi K, Michaud A, C.-Gaudreault R, Diorio C, Durocher F. TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer. Cancers (Basel) 2021; 13:3557. [PMID: 34298771 PMCID: PMC8304074 DOI: 10.3390/cancers13143557] [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: 06/14/2021] [Revised: 07/05/2021] [Accepted: 07/12/2021] [Indexed: 01/02/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a major concern among the different subtypes of breast cancer (BC) due to the lack of effective treatment. In a previous study by our group aimed at understanding the difference between TNBC and non-TNBC tumors, we identified the gene TBC1 domain family member 9 (TBC1D9), the expression of which was lower in TNBC as compared to non-TNBC tumors. In the present study, analysis of TBC1D9 expression in TNBC (n = 58) and non-TNBC (n = 25) patient tumor samples validated that TBC1D9 expression can differentiate TNBC (low) from non-TNBC (high) samples and that expression of TBC1D9 was inversely correlated with grade and proliferative index. Moreover, we found that downregulation of the TBC1D9 gene decreases the proliferation marginally in non-TNBC and was associated with increased migratory and tumorigenic potential in both TNBC and luminal BC cell lines. This increase was mediated by the upregulation of ARL8A, ARL8B, PLK1, HIF1α, STAT3, and SPP1 expression in TBC1D9 knockdown cells. Our results suggest that TBC1D9 expression might limit tumor aggressiveness and that it has a differential expression in TNBC vs. non-TNBC tumors.
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Affiliation(s)
- Charu Kothari
- Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec City, QC G1T 1C2, Canada; (C.K.); (A.C.); (G.O.); (R.C.-G.)
- Centre de Recherche sur le Cancer, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC G1V 4G2, Canada; (K.E.-I.); (A.M.); (C.D.)
| | - Alisson Clemenceau
- Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec City, QC G1T 1C2, Canada; (C.K.); (A.C.); (G.O.); (R.C.-G.)
- Centre de Recherche sur le Cancer, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC G1V 4G2, Canada; (K.E.-I.); (A.M.); (C.D.)
| | - Geneviève Ouellette
- Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec City, QC G1T 1C2, Canada; (C.K.); (A.C.); (G.O.); (R.C.-G.)
- Centre de Recherche sur le Cancer, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC G1V 4G2, Canada; (K.E.-I.); (A.M.); (C.D.)
| | - Kaoutar Ennour-Idrissi
- Centre de Recherche sur le Cancer, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC G1V 4G2, Canada; (K.E.-I.); (A.M.); (C.D.)
- Département de Biologie Moléculaire, de Biochimie Médicale et de Pathologie, Faculté de Médecine, Université Laval, Québec City, QC G1T 1C2, Canada
- Département de Médecine Sociale et Préventive, Faculté de Médecine, Université Laval, Québec City, QC G1T 1C2, Canada
| | - Annick Michaud
- Centre de Recherche sur le Cancer, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC G1V 4G2, Canada; (K.E.-I.); (A.M.); (C.D.)
| | - René C.-Gaudreault
- Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec City, QC G1T 1C2, Canada; (C.K.); (A.C.); (G.O.); (R.C.-G.)
- Centre de Recherche sur le Cancer, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC G1V 4G2, Canada; (K.E.-I.); (A.M.); (C.D.)
- Laboratoire de Chimie Médicinale, l’Hôpital Saint-François d’Assise, Université Laval, Québec City, QC G1L 3L5, Canada
| | - Caroline Diorio
- Centre de Recherche sur le Cancer, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC G1V 4G2, Canada; (K.E.-I.); (A.M.); (C.D.)
- Département de Médecine Sociale et Préventive, Faculté de Médecine, Université Laval, Québec City, QC G1T 1C2, Canada
- Centre des Maladies du Sein, Hôpital du Saint-Sacrement, Québec City, QC G1S 4L8, Canada
| | - Francine Durocher
- Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec City, QC G1T 1C2, Canada; (C.K.); (A.C.); (G.O.); (R.C.-G.)
- Centre de Recherche sur le Cancer, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC G1V 4G2, Canada; (K.E.-I.); (A.M.); (C.D.)
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20
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Kao CN, Moi SH, Hou MF, Luo CW, Chen FM, Pan MR. RNF8-CDH1 Co-Expression Predicts Clinical Benefit of Chemoradiotherapy in Triple-Negative Breast Cancer. J Pers Med 2021; 11:jpm11070655. [PMID: 34357122 PMCID: PMC8307233 DOI: 10.3390/jpm11070655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 01/16/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and exhibits an overall poor outcome. Due to the lack of targeted therapy, conventional systemic chemotherapy has been the main strategy for the treatment of TNBC. Further evidence has shown that combining radiation with chemotherapy is also a suitable treatment based on DNA repair deficiencies in patients with TNBC. However, the preferred treatment for metastatic TNBC remains unclear. Therefore, identification of biomarkers is an unmet need in personalized therapy for TNBC. RNF8 (ring finger protein 8) is a ubiquitin ligase implicated in TNBC metastasis; however, its role in TNBC pathogenesis is unclear. The purpose of the present study was to investigate the roles of the RNF8-CDH1(Cadherin 1) axis in node-positive TNBC patients. We found that the RNF8high/CDH1low index was significantly higher in patients with TNBC than in patients without TNBC. Furthermore, patients with an RNF8high/CDH1low index displayed poorer outcomes than those with an RNF8low-medium/CDH1medium-high index. Notably, as compared to patients with an RNF8low-medium/CDH1medium-high index, those with an RNF8high/CDH1low index had a poorer survival rate with chemotherapy treatment alone. The combination of radiation and chemotherapy resulted in a better survival rate than chemotherapy alone in patients with an RNF8high/CDH1low index. Taken together, the RNF8high/CDH1low index not only functions as a prognostic and therapeutic marker but may also act as a target in the development of anti-cancer agents for patients with TNBC.
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Affiliation(s)
- Chieh-Ni Kao
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-W.L.); (F.-M.C.)
| | - Sin-Hua Moi
- Center of Cancer Program Development, E-Da Cancer Hospital, I-Shou University, Kaohsiung 824, Taiwan;
| | - Ming-Feng Hou
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-W.L.); (F.-M.C.)
- Correspondence: (M.-F.H.); (M.-R.P.); Tel.: +886-7-3121101-6060 (M.-F.H.); +886-7-3121101-5092-94 (M.-R.P.); Fax: +886-7-3218309 (M.-R.P.)
| | - Chi-Wen Luo
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-W.L.); (F.-M.C.)
| | - Fang-Ming Chen
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-W.L.); (F.-M.C.)
| | - Mei-Ren Pan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: (M.-F.H.); (M.-R.P.); Tel.: +886-7-3121101-6060 (M.-F.H.); +886-7-3121101-5092-94 (M.-R.P.); Fax: +886-7-3218309 (M.-R.P.)
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21
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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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22
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Tazzite A, Jouhadi H, Benider A, Nadifi S. BRCA Mutational Status is a Promising Predictive Biomarker for Platinum- based Chemotherapy in Triple-Negative Breast Cancer. Curr Drug Targets 2021; 21:962-973. [PMID: 32013831 DOI: 10.2174/1389450121666200203162541] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 11/21/2019] [Accepted: 12/18/2019] [Indexed: 01/18/2023]
Abstract
Triple-negative breast cancer (TNBC) can be distinguished from other breast malignancies by the lack of expression of estrogen receptors (ER), progesterone receptors (PR) as well as human epidermal growth factor receptor 2 (HER2). TNBC is associated with adverse clinical outcomes and high risk of metastasis. Currently, several clinical and translational reports are focusing on developing targeted therapies for this aggressive cancer. In addition to approved targeted drugs such as poly(ADP-ribose) polymerase inhibitors (PARPi) and immune-checkpoint inhibitors, platinum-based chemotherapy is still a cornerstone therapeutic option in TNBC. However, despite the observed improved outcomes with platinum- based chemotherapy in TNBC, there is still a large proportion of patients who do not respond to this treatment, hence, the need for predictive biomarkers to stratify TNBC patients and therefore, avoiding unwanted toxicities of these agents. With the emergence of genetic testing, several recent studies suggested mutations in breast cancer susceptibility gene (BRCA) in TNBC patients as important predictors of outcomes. These mutations alter the homologous recombination repair (HRR) mechanisms leading to genomic instability. Consequently, sensitivity to platinum-based treatments in this subpopulation of TNBC patients may be explained by cell death enhanced by deoxyribonucleic acid (DNA) damage induced by these potent anticancer drugs. Through this paper, we review several recent studies on this topic to better understand the mechanisms and discuss the potential of BRCA mutational status as a predictive biomarker of platinum-based chemotherapy in TNBC.
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Affiliation(s)
- Amal Tazzite
- Genetics and Molecular Pathology Laboratory, Medical school of Casablanca, Hassan II University, Casablanca, Morocco
| | - Hassan Jouhadi
- Mohammed VI Center for Cancer Treatment, Ibn Rochd University Hospital, Casablanca, Morocco
| | - Abdellatif Benider
- Mohammed VI Center for Cancer Treatment, Ibn Rochd University Hospital, Casablanca, Morocco
| | - Sellama Nadifi
- Genetics and Molecular Pathology Laboratory, Medical school of Casablanca, Hassan II University, Casablanca, Morocco
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23
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Criscitiello C, Guerini-Rocco E, Viale G, Fumagalli C, Sajjadi E, Venetis K, Piciotti R, Invernizzi M, Malapelle U, Fusco N. Immunotherapy in Breast Cancer Patients: A Focus on the Use of the Currently Available Biomarkers in Oncology. Anticancer Agents Med Chem 2021; 22:787-800. [PMID: 34229592 DOI: 10.2174/1871520621666210706144112] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/23/2021] [Accepted: 02/01/2021] [Indexed: 11/22/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have remarkably modified the way solid tumors are managed, including breast cancer. Unfortunately, only a relatively small number of breast cancer patients significantly respond to these treatments. To maximize the immunotherapy benefit in breast cancer, several efforts are currently being put forward for the identification of i) the best therapeutic strategy (i.e. ICI monotherapy or in association with chemotherapy, radiotherapy, or other drugs); ii) the optimal timing for administration (e.g. early/advanced stage of disease; adjuvant/neoadjuvant setting); iii) the most effective and reliable predictive biomarkers of response (e.g. tumor-infiltrating lymphocytes, programmed death-ligand 1, microsatellite instability associated with mismatch repair deficiency, and tumor mutational burden). This article reviews the impacts and gaps in the characterization of immune-related biomarkers raised by clinical and translational research studies with immunotherapy treatments. Particular emphasis has been put on the documented evidence of significant clinical benefits of ICI in different randomized clinical trials, along with preanalytical and analytical issues in predictive biomarkers pathological assessment.
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Affiliation(s)
| | | | - Giulia Viale
- Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
| | - Caterina Fumagalli
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Elham Sajjadi
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | | | - Roberto Piciotti
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Marco Invernizzi
- Physical and Rehabilitative Medicine, Department of Health Sciences, University of Eastern Piedmont, Viale Piazza D'Armi 1, Novara, Italy
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Nicola Fusco
- Division of Pathology, IEO, European Institute of Oncology IRCCS, University of Milan, Via Giuseppe Ripamonti 435, 20141, Milan, Italy
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24
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Qi Y, Zhang L, Wang Z, Kong X, Zhai J, Fang Y, Wang J. Efficacy and Safety of Anti-PD-1/ PD-L1 Monotherapy for Metastatic Breast Cancer: Clinical Evidence. Front Pharmacol 2021; 12:653521. [PMID: 34267656 PMCID: PMC8276035 DOI: 10.3389/fphar.2021.653521] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/28/2021] [Indexed: 12/31/2022] Open
Abstract
Background: Success has been reported in PD-1/PD-L1 blockade via pembrolizumab, atezolizumab, or avelumab monotherapy in manifold malignancies including metastatic breast cancer. Due to lack of large-scale study, here we present interim analyses to evaluate the safety and efficacy of these promising strategies in patients with advanced breast cancer. Methods: Six studies including 586 advanced breast cancer patients treated with anti-PD-1/PD-L1 monotherapy agents before July 1, 2020, were included. The anti-PD-1/PD-L1 agents include pembrolizumab, atezolizumab, land avelumab. Statistics was analyzed by R software and IBM SPSS Statistics 22. Results: Global analysis showed that for this monotherapy, the complete response was 1.26%, partial response was 7.65%, objective response rate (ORR) was 9.85%, and disease control rate (DCR) was 18.33%. 1-year overall survival rate and 6-month progression-free survival rate were 43.34 and 17.24%. Overall incidence of adverse events (AEs) was 64.18% in any grade and 12.94% in severe grade, while the incidence of immune-related AEs (irAEs) was approximately 14.75%: the most common treatment-related AEs of any grade that occurred in at least 5% of patients were arthralgia and asthenia; the most common severe treatment-related AEs occurred in at least 1% of patients were anemia and autoimmune hepatitis; the most common irAEs were hypothyroidism. Besides, the incidence of discontinue and death due to treatment-related AEs was about 3.06 and 0.31%, respectively. Additionally, by comparing efficacy indicators between PD-L1-positive and PD-L1-negative groups, an implicated correspondence between efficacy and the expression of PD-L1 biomarker was found: the PR was 9.93 vs 2.69%; the ORR was 10.62 vs. 3.07%; the DCR was 17.95 vs. 4.71%. Conclusion: Anti-PD-1/PD-L1 monotherapy showed a manageable safety profile and had a promising and durable anti-tumor efficacy in metastatic breast cancer patients. Higher PD-L1 expression may be closely correlated to a better clinical efficacy.
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Affiliation(s)
- Yihang Qi
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Zhang
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.,Centre of Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia
| | - Zhongzhao Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Zhai
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Fang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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25
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Wang X, Wang L, Bu H, Zhang N, Yue M, Jia Z, Cai L, He J, Wang Y, Xu X, Li S, Xiao K, Yan K, Tian K, Han X, Huang J, Yao J, Liu Y. How can artificial intelligence models assist PD-L1 expression scoring in breast cancer: results of multi-institutional ring studies. NPJ Breast Cancer 2021; 7:61. [PMID: 34039982 PMCID: PMC8155065 DOI: 10.1038/s41523-021-00268-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 04/19/2021] [Indexed: 12/13/2022] Open
Abstract
Programmed death ligand-1 (PD-L1) expression is a key biomarker to screen patients for PD-1/PD-L1-targeted immunotherapy. However, a subjective assessment guide on PD-L1 expression of tumor-infiltrating immune cells (IC) scoring is currently adopted in clinical practice with low concordance. Therefore, a repeatable and quantifiable PD-L1 IC scoring method of breast cancer is desirable. In this study, we propose a deep learning-based artificial intelligence-assisted (AI-assisted) model for PD-L1 IC scoring. Three rounds of ring studies (RSs) involving 31 pathologists from 10 hospitals were carried out, using the current guideline in the first two rounds (RS1, RS2) and our AI scoring model in the last round (RS3). A total of 109 PD-L1 (Ventana SP142) immunohistochemistry (IHC) stained images were assessed and the role of the AI-assisted model was evaluated. With the assistance of AI, the scoring concordance across pathologists was boosted to excellent in RS3 (0.950, 95% confidence interval (CI): 0.936-0.962) from moderate in RS1 (0.674, 95% CI: 0.614-0.735) and RS2 (0.736, 95% CI: 0.683-0.789). The 2- and 4-category scoring accuracy were improved by 4.2% (0.959, 95% CI: 0.953-0.964) and 13% (0.815, 95% CI: 0.803-0.827) (p < 0.001). The AI results were generally accepted by pathologists with 61% "fully accepted" and 91% "almost accepted". The proposed AI-assisted method can help pathologists at all levels to improve the PD-L1 assay (SP-142) IC assessment in breast cancer in terms of both accuracy and concordance. The AI tool provides a scheme to standardize the PD-L1 IC scoring in clinical practice.
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Affiliation(s)
- Xinran Wang
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Liang Wang
- AI Lab, Tencent, Shenzhen, Guangdong, China
| | - Hong Bu
- Department of Pathology, West China Center of Medical Sciences, Sichuan University, Chengdu, Sichuan, China
| | - Ningning Zhang
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Meng Yue
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhanli Jia
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Lijing Cai
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jiankun He
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yanan Wang
- Department of Pathology, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Xin Xu
- Department of Pathology, Xingtai People's Hospital/Hebei Medical University Affiliated Hospital, Xingtai, Hebei, China
| | - Shengshui Li
- Department of Pathology, Cangzhou Hospital of Integrated TCM-WM, Cangzhou, Hebei, China
| | | | - Kezhou Yan
- AI Lab, Tencent, Shenzhen, Guangdong, China
| | - Kuan Tian
- AI Lab, Tencent, Shenzhen, Guangdong, China
| | - Xiao Han
- AI Lab, Tencent, Shenzhen, Guangdong, China
| | | | - Jianhua Yao
- AI Lab, Tencent, Shenzhen, Guangdong, China.
| | - Yueping Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
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26
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Effects of Water Extract of Cynanchum paniculatum (Bge.) Kitag. on Different Breast Cancer Cell Lines. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6665949. [PMID: 34122605 PMCID: PMC8172293 DOI: 10.1155/2021/6665949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/13/2021] [Accepted: 03/10/2021] [Indexed: 11/18/2022]
Abstract
Cynanchum paniculatum (Bge.) Kitag. (CP) is an important medicinal herb used in Chinese herbal medicine, with a variety of biological activities including anticancer property. In this study, we explored the water extract of CP, for its anticancer effects against breast cancer cells with different mutation types. Cells were grouped as untreated (Control); CP direct treatment (dir-CP); Conditioned medium from CP treated (sup-CP), and untreated cells (sup-Control). Effects of dir-CP and sup-CP were compared to corresponding untreated cells on cytotoxicity, cell migration, and protein expression (cleaved caspase-3, caspase-9, and MMP-2 and 9). CP treatment showed time-dependent decrease in cell number of MDA-MB-231 and SK-Br-3 (both ER(−) PR(−)), while the decrease in cell number was not as significant in MCF-7 and ZR-75-1 cells (both ER(+) PR(+)). sup-CP treatment inhibited the cell migration of MDA-MB-231 and MCF-7 (Her2(−)) in a 24 h scratch assay. Our data suggested that ER(−) PR(−) cells are more sensitive to the CP in terms of direct cytotoxicity, which is not regulated by caspase-3. CP inhibited the migration of the two Her2(−) cells, and this correlated with MMP-2 regulation. The migration of ER(−) PR(−) cells was more sensitive to conditioned medium with CP treatment than to direct CP, and this is not regulated by MMP-2. Our data suggested that CP has anticancer potential on various breast cancer cells through different mechanisms and is specifically effective in inhibiting the migration of the triple negative MDA-MB-231. Our data provide insight into the mechanism of CP against breast cancer progression and would benefit the medical practitioners in better management with CP usage.
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27
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Tjo K, Varamini P. Nanodiamonds and their potential applications in breast cancer therapy: a narrative review. Drug Deliv Transl Res 2021; 12:1017-1028. [PMID: 33970463 DOI: 10.1007/s13346-021-00996-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2021] [Indexed: 12/24/2022]
Abstract
Breast cancer remains the most commonly diagnosed cancer and the leading cause of cancer-related death among women worldwide. With the projected increase in breast cancer cases in recent years, optimising treatment becomes increasingly important. Current treatment modalities in breast cancer present major limitations, including chemoresistance, dose-limiting adverse effects and lack of selectivity in aggressive subtypes of breast cancers such as triple-negative breast cancer. Nanodiamonds have demonstrated promising outcomes in preclinical models from their unique surface characteristics allowing optimised delivery of various therapeutic agents, overcoming some of the significant hurdles in conventional treatment modalities. This review will present an update on preclinical findings of nanodiamond-based drug delivery systems for breast cancer therapy to date, challenges with the use of nanodiamonds along with considerations for future research.
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Affiliation(s)
- Kenny Tjo
- Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2016, Australia
| | - Pegah Varamini
- Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2016, Australia. .,Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
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28
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Vito A, Rathmann S, Mercanti N, El-Sayes N, Mossman K, Valliant J. Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer. Int J Mol Sci 2021; 22:4843. [PMID: 34063642 PMCID: PMC8124136 DOI: 10.3390/ijms22094843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/28/2021] [Accepted: 05/01/2021] [Indexed: 01/22/2023] Open
Abstract
Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low, and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabeled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.
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Affiliation(s)
- Alyssa Vito
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada; (A.V.); (N.E.-S.)
| | - Stephanie Rathmann
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4K1, Canada; (S.R.); (N.M.)
| | - Natalie Mercanti
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4K1, Canada; (S.R.); (N.M.)
| | - Nader El-Sayes
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada; (A.V.); (N.E.-S.)
| | - Karen Mossman
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada; (A.V.); (N.E.-S.)
| | - John Valliant
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4K1, Canada; (S.R.); (N.M.)
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29
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Tamura Y, Morikawa M, Tanabe R, Miyazono K, Koinuma D. Anti-pyroptotic function of TGF-β is suppressed by a synthetic dsRNA analogue in triple negative breast cancer cells. Mol Oncol 2021; 15:1289-1307. [PMID: 33342034 PMCID: PMC8096786 DOI: 10.1002/1878-0261.12890] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/27/2020] [Accepted: 12/17/2020] [Indexed: 12/11/2022] Open
Abstract
Development of innovative therapeutic modalities would address an unmet clinical need in the treatment of triple negative breast cancer (TNBC). Activation of retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) such as melanoma differentiation-associated gene 5 (MDA5) and RIG-I in cancer cells is suggested to suppress tumor progression by inducing cell death. Transfection of polyI:C, a conventionally used synthetic double-stranded RNA (dsRNA) analogue that activates RLRs, has been evaluated in clinical trials. However, detailed mechanisms of tumor suppression by RLRs, especially interactions with other signaling pathways, remain elusive. Here, we showed that transfection of polyI:C suppressed transforming growth factor-β (TGF-β) signaling in a MDA5- and RIG-I-dependent manner. We found that suppression of TGF-β signaling by polyI:C promoted cancer cell death, which was attenuated by forced expression of constitutively active Smad3. More detailed analysis suggested that cell death by polyI:C transfection exhibited characteristics of pyroptosis, which is distinct from apoptosis. Therapeutic efficacy of polyI:C transfection was also demonstrated using a mouse model. These results indicated that intratumor administration of polyI:C and related dsRNA analogues may be promising treatments for TNBC through inhibition of the anti-pyroptotic function of TGF-β.
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Affiliation(s)
- Yusuke Tamura
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
| | - Masato Morikawa
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
| | - Ryo Tanabe
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
| | - Kohei Miyazono
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
| | - Daizo Koinuma
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
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30
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Fang H, Cavaliere A, Li Z, Huang Y, Marquez-Nostra B. Preclinical Advances in Theranostics for the Different Molecular Subtypes of Breast Cancer. Front Pharmacol 2021; 12:627693. [PMID: 33986665 PMCID: PMC8111013 DOI: 10.3389/fphar.2021.627693] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/22/2021] [Indexed: 12/29/2022] Open
Abstract
Breast cancer is the most common cancer in women worldwide. The heterogeneity of breast cancer and drug resistance to therapies make the diagnosis and treatment difficult. Molecular imaging methods with positron emission tomography (PET) and single-photon emission tomography (SPECT) provide useful tools to diagnose, predict, and monitor the response of therapy, contributing to precision medicine for breast cancer patients. Recently, many efforts have been made to find new targets for breast cancer therapy to overcome resistance to standard of care treatments, giving rise to new therapeutic agents to offer more options for patients with breast cancer. The combination of diagnostic and therapeutic strategies forms the foundation of theranostics. Some of these theranostic agents exhibit high potential to be translated to clinic. In this review, we highlight the most recent advances in theranostics of the different molecular subtypes of breast cancer in preclinical studies.
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Affiliation(s)
- Hanyi Fang
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States.,Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Alessandra Cavaliere
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States
| | - Ziqi Li
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States.,Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiyun Huang
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States
| | - Bernadette Marquez-Nostra
- PET Center, Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, United States
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31
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Gao C, Li H, Liu C, Xu X, Zhuang J, Zhou C, Liu L, Feng F, Sun C. Tumor Mutation Burden and Immune Invasion Characteristics in Triple Negative Breast Cancer: Genome High-Throughput Data Analysis. Front Immunol 2021; 12:650491. [PMID: 33968045 PMCID: PMC8097167 DOI: 10.3389/fimmu.2021.650491] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 04/01/2021] [Indexed: 12/14/2022] Open
Abstract
In recent years, the emergence of immunotherapy has provided a new perspective for the treatment and management of triple-negative breast cancer (TNBC). However, the relationship between tumor mutation burden (TMB) and immune infiltration and the prognosis of TNBC remains unclear. In this study, to explore the immunogenicity of TNBC, we divided patients with TNBC into high and low TMB groups based on the somatic mutation data of TNBC in The Cancer Genome Atlas (TCGA), and screened out genes with mutation rate ≥10. Then, Kaplan-Meier survival analysis revealed that the 5-year survival rate of the high TMB group was much higher than that of the low TMB group and the two groups also showed differences in immune cell infiltration. Further exploration found that the FAT3 gene, which displays significant difference and a higher mutation rate between the two groups, is not only significantly related to the prognosis of TNBC patients but also exhibits difference in immune cell infiltration between the wild group and the mutant group of the FAT3 gene. The results of gene set enrichment analysis and drug sensitivity analysis further support the importance of the FAT3 gene in TNBC. This study reveals the characteristics of TMB and immune cell infiltration in triple-negative breast cancer and their relationship with prognosis, to provide new biomarkers and potential treatment options for the future treatment of TNBC. The FAT3 gene, as a risk predictor gene of TNBC, is considered a potential biological target and may provide new insight for the treatment of TNBC.
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Affiliation(s)
- Chundi Gao
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Huayao Li
- College of Basic Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Cun Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaowei Xu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jing Zhuang
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China
| | - Chao Zhou
- College of Basic Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lijuan Liu
- College of Basic Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fubin Feng
- College of Basic Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Changgang Sun
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China.,Qingdao Academy of Chinese Medical Sciences, Shandong University of Traditional Chinese Medicine, Qingdao, China
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32
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Elimimian EB, Samuel TA, Liang H, Elson L, Bilani N, Nahleh ZA. Clinical and Demographic Factors, Treatment Patterns, and Overall Survival Associated With Rare Triple-Negative Breast Carcinomas in the US. JAMA Netw Open 2021; 4:e214123. [PMID: 33844001 PMCID: PMC8042532 DOI: 10.1001/jamanetworkopen.2021.4123] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
IMPORTANCE Triple-negative breast cancers are known collectively to demonstrate a more aggressive clinical course and earlier recurrence than cancers of other histological subtypes. However, the literature on rare triple-negative breast cancers and the association of histological type with survival and risk of metastasis is sparse. OBJECTIVE To present the clinical and demographic characteristics, treatment patterns, and overall survival (OS) for histologically rare (<10% of breast cancers) triple-negative breast cancer types: medullary carcinoma, adenoid cystic carcinoma, and metaplastic breast carcinoma. DESIGN, SETTING, AND PARTICIPANTS This cohort study was performed in the US using data reported by the National Cancer Database between 2010 and 2016. Confirmed cases of medullary carcinoma, adenoid cystic carcinoma, and metaplastic breast cancer were analyzed. Univariable analyses and multivariable Cox regression models were performed. Data analysis was performed from April to May 2020. MAIN OUTCOMES AND MEASURES The primary outcome was 5-year OS. Secondary outcomes included site of metastasis, effect of immunohistochemistry, management, and 2-year mortality. RESULTS A total of 8479 patients with breast cancer (mean [SD] age; 62.6 [14.3] years; 8435 women [99.48%]) were analyzed. Metaplastic carcinoma was the most commonly diagnosed histological type in this cohort, with 6867 patients (81%), followed by 1357 (16%) with adenoid cystic carcinoma and only 255 (3%) with medullary carcinoma. Medullary carcinoma presented earlier in life, at a median (interquartile range) age of 53 (45-62) years, compared with 62 (53-72) years for patients with adenoid cystic carcinoma and 63 (52-74) years for patients with metaplastic carcinoma. The proportion of tumors with triple-negative immunohistochemistry varied by histological type for medullary carcinoma (57 patients [22.4%]), adenoid cystic carcinoma (653 patients [48.1%]), and metaplastic carcinoma (3637 patients [53.0%]). Patients with adenoid cystic carcinoma were less likely to receive radiotherapy (711 patients [52.4%]) and chemotherapy (175 patients [12.9%]) compared with patients with medullary carcinoma (radiotherapy, 156 patients [61.2%]; chemotherapy, 190 patients [74.5%]) and metaplastic carcinoma (radiotherapy, 3416 patients [49.7%]; chemotherapy, 4709 patients [68.6%]). The 5-year OS rate was superior for patients with medullary (91.7%) and adenoid cystic carcinoma (88.4%) compared with patients with metaplastic carcinoma (63.1%). The 5-year mortality rate for adenoid cystic carcinoma was 8.33% vs 36.91% for metaplastic carcinoma. CONCLUSIONS AND RELEVANCE Nationally, over the course of 7 years, medullary carcinoma was most common and metaplastic carcinoma had the worst 5-year OS among the rare histological breast cancer subtypes analyzed. Factors associated with a poor prognosis for metaplastic carcinoma included advanced stage, lung metastasis, older age, and not receiving chemotherapy or radiation therapy. Future research focusing on rare subtypes of breast cancer is desirable and could inform the optimal management of these relatively understudied carcinomas.
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Affiliation(s)
- Elizabeth B. Elimimian
- Department of Hematology-Oncology, Maroone Cancer Center, Cleveland Clinic Florida, Weston, Florida
| | - Thomas A. Samuel
- Department of Hematology-Oncology, Maroone Cancer Center, Cleveland Clinic Florida, Weston, Florida
| | - Hong Liang
- Department of Hematology-Oncology, Maroone Cancer Center, Cleveland Clinic Florida, Weston, Florida
| | - Leah Elson
- Department of Hematology-Oncology, Maroone Cancer Center, Cleveland Clinic Florida, Weston, Florida
| | - Nadeem Bilani
- Department of Hematology-Oncology, Maroone Cancer Center, Cleveland Clinic Florida, Weston, Florida
| | - Zeina A. Nahleh
- Department of Hematology-Oncology, Maroone Cancer Center, Cleveland Clinic Florida, Weston, Florida
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33
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Cao X, Li B, Chen J, Dang J, Chen S, Gunes EG, Xu B, Tian L, Muend S, Raoof M, Querfeld C, Yu J, Rosen ST, Wang Y, Feng M. Effect of cabazitaxel on macrophages improves CD47-targeted immunotherapy for triple-negative breast cancer. J Immunother Cancer 2021; 9:jitc-2020-002022. [PMID: 33753567 PMCID: PMC7986678 DOI: 10.1136/jitc-2020-002022] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2021] [Indexed: 12/12/2022] Open
Abstract
Background Limited therapeutic options are available for triple-negative breast cancer (TNBC), emphasizing an urgent need for more effective treatment approaches. The development of strategies by targeting tumor-associated macrophages (TAMs) to stimulate their ability of Programmed Cell Removal (PrCR) provides a promising new immunotherapy for TNBC treatment. Methods CD47 is a critical self-protective “don’t eat me” signal on multiple human cancers against macrophage immunosurveillance. Using human and mouse TNBC preclinical models, we evaluated the efficacy of PrCR-based immunotherapy by blocking CD47. We performed high-throughput screens on FDA-approved anti-cancer small molecule compounds for agents potentiating PrCR and enhancing the efficacy of CD47-targeted therapy for TNBC treatment. Results We showed that CD47 was widely expressed on TNBC cells and TAMs represented the most abundant immune cell population in TNBC tumors. Blockade of CD47 enabled PrCR of TNBC cells, but the efficacy was not satisfactory. Our high-throughput screens identified cabazitaxel in enhancing PrCR-based immunotherapy. A combination of CD47 blockade and cabazitaxel treatment yielded a highly effective treatment strategy, promoting PrCR of TNBC cells and inhibiting tumor development and metastasis in preclinical models. We demonstrated that cabazitaxel potentiated PrCR by activating macrophages, independent of its cytotoxicity toward cancer cells. When treated with cabazitaxel, the molecular and phenotypic signatures of macrophages were polarized toward M1 state, and the NF-kB signaling pathway became activated. Conclusion The combination of CD47 blockade and macrophage activation by cabazitaxel synergizes to vastly enhance the elimination of TNBC cells. Our results show that targeting macrophages is a promising and effective strategy for TNBC treatment.
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Affiliation(s)
- Xu Cao
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA
| | - Bolei Li
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA
| | - Jing Chen
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA
| | - Jessica Dang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA
| | - Siqi Chen
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA
| | - E Gulsen Gunes
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA.,Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Bo Xu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA.,Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Lei Tian
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA.,Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Sabina Muend
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA
| | - Mustafa Raoof
- Department of Surgery, City of Hope, Duarte, California, USA
| | - Christiane Querfeld
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA.,Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA.,Division of Dermatology, City of Hope, Duarte, California, USA.,Department of Pathology, City of Hope, Duarte, California, USA
| | - Jianhua Yu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA.,Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA.,Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, California, USA
| | - Steven T Rosen
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA.,Beckman Research Institute, City of Hope, Duarte, California, USA
| | - Yingyu Wang
- Center for Informatics, City of Hope, Duarte, California, USA
| | - Mingye Feng
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California, USA
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34
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Wang H, Ma H, Sové RJ, Emens LA, Popel AS. Quantitative systems pharmacology model predictions for efficacy of atezolizumab and nab-paclitaxel in triple-negative breast cancer. J Immunother Cancer 2021; 9:jitc-2020-002100. [PMID: 33579739 PMCID: PMC7883871 DOI: 10.1136/jitc-2020-002100] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2021] [Indexed: 12/18/2022] Open
Abstract
Background Immune checkpoint blockade therapy has clearly shown clinical activity in patients with triple-negative breast cancer, but less than half of the patients benefit from the treatments. While a number of ongoing clinical trials are investigating different combinations of checkpoint inhibitors and chemotherapeutic agents, predictive biomarkers that identify patients most likely to benefit remains one of the major challenges. Here we present a modular quantitative systems pharmacology (QSP) platform for immuno-oncology that incorporates detailed mechanisms of immune–cancer cell interactions to make efficacy predictions and identify predictive biomarkers for treatments using atezolizumab and nab-paclitaxel. Methods A QSP model was developed based on published data of triple-negative breast cancer. With the model, we generated a virtual patient cohort to conduct in silico virtual clinical trials and make retrospective analyses of the pivotal IMpassion130 trial that led to the accelerated approval of atezolizumab and nab-paclitaxel for patients with programmed death-ligand 1 (PD-L1) positive triple-negative breast cancer. Available data from clinical trials were used for model calibration and validation. Results With the calibrated virtual patient cohort based on clinical data from the placebo comparator arm of the IMpassion130 trial, we made efficacy predictions and identified potential predictive biomarkers for the experimental arm of the trial using the proposed QSP model. The model predictions are consistent with clinically reported efficacy endpoints and correlated immune biomarkers. We further performed a series of virtual clinical trials to compare different doses and schedules of the two drugs for simulated therapeutic optimization. Conclusions This study provides a QSP platform, which can be used to generate virtual patient cohorts and conduct virtual clinical trials. Our findings demonstrate its potential for making efficacy predictions for immunotherapies and chemotherapies, identifying predictive biomarkers, and guiding future clinical trial designs.
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Affiliation(s)
- Hanwen Wang
- Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Huilin Ma
- Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Richard J Sové
- Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Leisha A Emens
- Department of Medicine, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Aleksander S Popel
- Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.,Department of Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
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35
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Núñez Abad M, Calabuig-Fariñas S, Lobo de Mena M, José Godes Sanz de Bremond M, García González C, Torres Martínez S, García-García JÁ, Iranzo González-Cruz V, Camps Herrero C. Update on systemic treatment in early triple negative breast cancer. Ther Adv Med Oncol 2021; 13:1758835920986749. [PMID: 33613695 PMCID: PMC7871289 DOI: 10.1177/1758835920986749] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/18/2020] [Indexed: 12/21/2022] Open
Abstract
Triple negative breast cancer (TNBC) is a heterogeneous disease representing about 15% of all breast cancers. TNBC are usually high-grade histological tumors, and are generally more aggressive and difficult to treat due to the lack of targeted therapies available, and chemotherapy remains the standard treatment. There is a close relationship between pathological complete response after chemotherapy treatment and higher rates of disease-free survival and overall survival. In this review of systemic treatment in early triple negative breast cancer, our purpose is to analyze and compare different therapies, as well as to highlight the novelties of treatment in this breast cancer subtype.
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Affiliation(s)
- Martín Núñez Abad
- Department of Medical Oncology, University
General Hospital of Valencia, Valencia, Spain
| | - Silvia Calabuig-Fariñas
- Molecular Oncology Laboratory, General
University Hospital Research Foundation, University General Hospital of
Valencia, Valencia, Spain
- CIBERONC, Madrid, Spain
- Department of Pathology, Universitat de
València, Valencia, Spain
- Mixed Unit TRIAL, Príncipe Felipe Research
Center & General University Hospital of Valencia Research Foundation,
Spain
| | - Miriam Lobo de Mena
- Department of Medical Oncology, University
General Hospital of Valencia, Valencia, Spain
| | | | - Clara García González
- Department of Medical Oncology, University
General Hospital of Valencia, Valencia, Spain
| | - Susana Torres Martínez
- Molecular Oncology Laboratory, General
University Hospital Research Foundation, University General Hospital of
Valencia, Valencia, Spain
- CIBERONC, Madrid, Spain
| | | | - Vega Iranzo González-Cruz
- Department of Medical Oncology, University
General Hospital of Valencia, Tres Cruces, 2, Valencia, 46014, Spain
- CIBERONC
- Department of Medicine, Universitat de
València, Valencia, Spain
| | - Carlos Camps Herrero
- Department of Medical Oncology, University
General Hospital of Valencia, Valencia, Spain
- Molecular Oncology Laboratory, General
University Hospital Research Foundation, University General Hospital of
Valencia, Valencia, Spain
- CIBERONC, Madrid, Spain
- Department of Medicine, Universitat de
València, Valencia, Spain
- Mixed Unit TRIAL, Príncipe Felipe Research
Center & General University Hospital of Valencia Research Foundation,
Spain
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36
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Determining Factors in the Therapeutic Success of Checkpoint Immunotherapies against PD-L1 in Breast Cancer: A Focus on Epithelial-Mesenchymal Transition Activation. J Immunol Res 2021; 2021:6668573. [PMID: 33506060 PMCID: PMC7808819 DOI: 10.1155/2021/6668573] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/17/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is the most common neoplasm diagnosed in women around the world. Checkpoint inhibitors, targeting the programmed death receptor-1 or ligand-1 (PD-1/PD-L1) axis, have dramatically changed the outcome of cancer treatment. These therapies have been recently considered as alternatives for treatment of breast cancers, in particular those with the triple-negative phenotype (TNBC). A further understanding of the regulatory mechanisms of PD-L1 expression is required to increase the benefit of PD-L1/PD-1 checkpoint immunotherapy in breast cancer patients. In this review, we will compile the most recent studies evaluating PD-1/PD-L1 checkpoint inhibitors in breast cancer. We review factors that determine the therapeutic success of PD-1/PD-L1 immunotherapies in this pathology. In particular, we focus on pathways that interconnect the epithelial-mesenchymal transition (EMT) with regulation of PD-L1 expression. We also discuss the relationship between cellular metabolic pathways and PD-L1 expression that are involved in the promotion of resistance in TNBC.
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Atezolizumab (in Combination with Nab-Paclitaxel): A Review in Advanced Triple-Negative Breast Cancer. Drugs 2020; 80:601-607. [PMID: 32248356 DOI: 10.1007/s40265-020-01295-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Atezolizumab (Tecentriq®), an immune checkpoint inhibitor against programmed death ligand 1 (PD-L1), is the first immunotherapy agent to be approved (for use in combination with nab-paclitaxel) in the USA, the EU (as first-line) and Japan for the treatment of advanced triple-negative breast cancer (TNBC). Approval was based on the results of the phase III IMpassion130 trial in patients with unresectable locally advanced or metastatic TNBC, in which atezolizumab plus nab-paclitaxel significantly prolonged progression-free survival (PFS) when compared to placebo plus nab-paclitaxel in the intent-to-treat (ITT) population and the PD-L1+ subgroup. Statistically significant overall survival (OS) benefits were not seen in two interim analyses and final OS data are awaited. The tolerability and safety profile of atezolizumab plus nab-paclitaxel was consistent with those of each individual drug. The most common treatment-related adverse events included neutropenia, peripheral neuropathy and reduced neutrophil count. Adverse events of special interest occurred with higher frequency in patients who received atezolizumab plus nab-paclitaxel than placebo plus nab-paclitaxel, and were mostly immune-related (e.g. immune-related rash, hypothyroidism and hepatitis). Health-related quality of life was not significantly impacted by the addition of atezolizumab to nab-paclitaxel therapy. Thus, atezolizumab plus nab-paclitaxel is a useful immunochemotherapy option for patients with unresectable locally advanced or metastatic TNBC, including those whose tumours have PD-L1 expression ≥ 1%.
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Ertay A, Liu H, Liu D, Peng P, Hill C, Xiong H, Hancock D, Yuan X, Przewloka MR, Coldwell M, Howell M, Skipp P, Ewing RM, Downward J, Wang Y. WDHD1 is essential for the survival of PTEN-inactive triple-negative breast cancer. Cell Death Dis 2020; 11:1001. [PMID: 33221821 PMCID: PMC7680459 DOI: 10.1038/s41419-020-03210-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 11/02/2020] [Accepted: 11/05/2020] [Indexed: 12/24/2022]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks the oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, making it difficult to target therapeutically. Targeting synthetic lethality is an alternative approach for cancer treatment. TNBC shows frequent loss of phosphatase and tensin homologue (PTEN) expression, which is associated with poor prognosis and treatment response. To identify PTEN synthetic lethal interactions, TCGA analysis coupled with a whole-genome siRNA screen in isogenic PTEN-negative and -positive cells were performed. Among the candidate genes essential for the survival of PTEN-inactive TNBC cells, WDHD1 (WD repeat and high-mobility group box DNA-binding protein 1) expression was increased in the low vs. high PTEN TNBC samples. It was also the top hit in the siRNA screen and its knockdown significantly inhibited cell viability in PTEN-negative cells, which was further validated in 2D and 3D cultures. Mechanistically, WDHD1 is important to mediate a high demand of protein translation in PTEN-inactive TNBC. Finally, the importance of WDHD1 in TNBC was confirmed in patient samples obtained from the TCGA and tissue microarrays with clinic-pathological information. Taken together, as an essential gene for the survival of PTEN-inactive TNBC cells, WDHD1 could be a potential biomarker or a therapeutic target for TNBC.
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Affiliation(s)
- Ayse Ertay
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
| | - Huiquan Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Dian Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Ping Peng
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Charlotte Hill
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
| | - Hua Xiong
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - David Hancock
- Oncogene Biology, The Francis Crick Institute, London, NW1 1AT, UK
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Marcin R Przewloka
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
| | - Mark Coldwell
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
| | - Michael Howell
- High-Throughput Screening, The Francis Crick Institute, London, NW1 1AT, UK
| | - Paul Skipp
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
- Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
| | - Rob M Ewing
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
| | - Julian Downward
- Oncogene Biology, The Francis Crick Institute, London, NW1 1AT, UK.
| | - Yihua Wang
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
- Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, SO16 6YD, UK.
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Amirkhani Namagerdi A, d'Angelo D, Ciani F, Iannuzzi CA, Napolitano F, Avallone L, De Laurentiis M, Giordano A. Triple-Negative Breast Cancer Comparison With Canine Mammary Tumors From Light Microscopy to Molecular Pathology. Front Oncol 2020; 10:563779. [PMID: 33282730 PMCID: PMC7689249 DOI: 10.3389/fonc.2020.563779] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/19/2020] [Indexed: 12/12/2022] Open
Abstract
Many similar characteristics in human and dog cancers including, spontaneous development, clinical presentation, tumor heterogeneity, disease progression, and response to standard therapies have promoted the approval of this comparative model as an alternative to mice. Breast cancer represents the second most frequent neoplasm in humans after lung cancer. Triple-negative breast cancers (TNBC) constitute around 15% of all cases of breast cancer and do not express estrogen receptor (ER), progesterone receptor (PR), and do not overexpress human epidermal growth factor receptor 2 (HER2). As a result, they do not benefit from hormonal or trastuzumab-based therapy. Patients with TNBC have worse overall survival than patients with non-TNBC. Lehmann and collaborators described six different molecular subtypes of TNBC which further demonstrated its transcriptional heterogeneity. This six TNBC subtype classification has therapeutic implications. Breast cancer is the second most frequent neoplasm in sexually intact female dogs after skin cancer. Canine mammary tumors are a naturally occurring heterogeneous group of cancers that have several features in common with human breast cancer (HBC). These similarities include etiology, signaling pathway activation, and histological classification. Molecularly CMTs are more like TNBCs, and therefore dogs are powerful spontaneous models of cancer to test new therapeutic approaches, particularly for human TNBCs. More malignant tumors of the breast are more often ER and PR negative in both humans and dogs. Promising breast cancer biomarkers in both humans and canines are cancer-associated stroma (CAS), circulating tumor cells and tumor DNA (ctDNA), exosomes and miRNAs, and metabolites.
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Affiliation(s)
| | - Danila d'Angelo
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy
| | - Francesca Ciani
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy
| | | | - Francesco Napolitano
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy.,CCEINGE, Biotecnologie Avanzate, Naples, Italy
| | - Luigi Avallone
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy
| | - Michelino De Laurentiis
- Breast Oncology Division, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Antonio Giordano
- Center for Biotechnology, College of Science and Technology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United States.,Department of Medical Biotechnologies, University of Siena, Siena, Italy
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40
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Female Malignancies and Immunotherapy: What's New? Cancers (Basel) 2020; 12:cancers12102909. [PMID: 33050485 PMCID: PMC7600966 DOI: 10.3390/cancers12102909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 10/07/2020] [Indexed: 11/17/2022] Open
Abstract
For many years, the therapeutic advances in gynecological neoplasms have remained steady, however, in recent years, the application of the most modern "-omics" sciences has shed light on the pathogenesis and on neoplastic progression, with important implications in the introduction of targeted treatments that are more effective and less toxic [...].
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41
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Zander H, Müller-Egert S, Zwiewka M, Groß S, van Zandbergen G, Engelbergs J. [Checkpoint inhibitors for cancer therapy]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020; 63:1322-1330. [PMID: 33001218 PMCID: PMC7648013 DOI: 10.1007/s00103-020-03221-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 09/04/2020] [Indexed: 12/17/2022]
Abstract
In recent years, a breakthrough in tumor therapy was achieved with the development of checkpoint inhibitors. Checkpoint inhibitors activate the immune defense against tumors by overcoming the inhibitory effect of specific cell surface proteins acting as control points, the so-called checkpoints. This article provides an overview of the mode of action of approved checkpoint inhibitors and the status of current clinical development.The previously approved checkpoint inhibitors, monoclonal antibodies directed against the checkpoints CTLA‑4 and PD-1/PD-L1, are used in various tumor entities (including lung, kidney, and urothelial carcinoma; head and neck cancer; melanoma; and Hodgkin lymphoma). For the first time, long-term survival has been achieved in some of these patients with advanced tumors. Unfortunately, this efficacy can be observed only in a small proportion of the treated patients, depending on the tumor indication. Improved efficacy is envisioned by patient selection via predictive biomarkers and the development of combination therapies. Mandatory testing of the expression level of the predictive PD-L1 biomarker is already required in some indications to select patients with an enhanced benefit/risk relationship.
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Affiliation(s)
- Hilke Zander
- Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-56, 63225, Langen, Deutschland
| | | | - Michal Zwiewka
- Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-56, 63225, Langen, Deutschland
| | - Steffen Groß
- Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-56, 63225, Langen, Deutschland
| | - Ger van Zandbergen
- Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-56, 63225, Langen, Deutschland
| | - Jörg Engelbergs
- Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-56, 63225, Langen, Deutschland.
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Gupta I, Rizeq B, Vranic S, Moustafa AEA, Al Farsi H. Circulating miRNAs in HER2-Positive and Triple Negative Breast Cancers: Potential Biomarkers and Therapeutic Targets. Int J Mol Sci 2020; 21:E6750. [PMID: 32942528 PMCID: PMC7554858 DOI: 10.3390/ijms21186750] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/02/2020] [Accepted: 09/06/2020] [Indexed: 12/14/2022] Open
Abstract
Breast cancer is one of the most prevalent diseases among women worldwide and is highly associated with cancer-related mortality. Of the four major molecular subtypes, HER2-positive and triple-negative breast cancer (TNBC) comprise more than 30% of all breast cancers. While the HER2-positive subtype lacks estrogen and progesterone receptors and overexpresses HER2, the TNBC subtype lacks estrogen, progesterone and HER2 receptors. Although advances in molecular biology and genetics have substantially ameliorated breast cancer disease management, targeted therapies for the treatment of estrogen-receptor negative breast cancer patients are still restricted, particularly for TNBC. On the other hand, it has been demonstrated that microRNAs, miRNAs or small non-coding RNAs that regulate gene expression are involved in diverse biological processes, including carcinogenesis. Moreover, circulating miRNAs in serum/plasma are among the most promising diagnostic/therapeutic tools as they are stable and relatively easy to quantify. Various circulating miRNAs have been identified in several human cancers including specific breast cancer subtypes. This review aims to discuss the role of circulating miRNAs as potential diagnostic and prognostic biomarkers as well as therapeutic targets for estrogen-receptor negative breast cancers, HER2+ and triple negative.
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Affiliation(s)
- Ishita Gupta
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (I.G.); (B.R.); (S.V.)
- Biomedical Research Centre, Qatar University, Doha P.O. Box 2713, Qatar
| | - Balsam Rizeq
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (I.G.); (B.R.); (S.V.)
- Biomedical Research Centre, Qatar University, Doha P.O. Box 2713, Qatar
| | - Semir Vranic
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (I.G.); (B.R.); (S.V.)
| | - Ala-Eddin Al Moustafa
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (I.G.); (B.R.); (S.V.)
- Biomedical Research Centre, Qatar University, Doha P.O. Box 2713, Qatar
| | - Halema Al Farsi
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (I.G.); (B.R.); (S.V.)
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Triple negative metaplastic breast carcinoma presenting in the background of atypical microglandular adenosis with candidacy for atezolizumab immunotherapy. HUMAN PATHOLOGY: CASE REPORTS 2020. [DOI: 10.1016/j.ehpc.2020.200398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Choi J, Lee HJ, Yoon S, Ryu HM, Lee E, Jo Y, Seo S, Kim D, Lee CH, Kim W, Ha JY, Kim SY, Gong G, Jung KH, Park SR, Kim SW, Park KS, Lee DH. Blockade of CCL2 expression overcomes intrinsic PD-1/PD-L1 inhibitor-resistance in transglutaminase 2-induced PD-L1 positive triple negative breast cancer. Am J Cancer Res 2020; 10:2878-2894. [PMID: 33042623 PMCID: PMC7539780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 08/09/2020] [Indexed: 06/11/2023] Open
Abstract
Anti-PD-1/PD-L1 immunotherapy, as a treatment for many tumors, has shown good efficacy. However, responses to immunotherapy did not always occur or last long., i.e. primary or acquired resistance, even tumors were PD-L1 positive. Several oncogenic pathways, including PI3K/AKT activation by PTEN loss and NF-κB activation, induce PD-L1 expression and PD-L1 inhibitor-resistance. They also induce expression of CCL2, an inhibitory chemokine that blocks T cell tracking into the tumor by binding to CCR2 on the T cell surface. In this study, we showed that transglutaminase 2 (TG2), a post-translational modification enzyme, induced ubiquitin-proteasome dependent degradation of tumor suppressors including PTEN and IκBα by peptide cross-linking, inducing CCL2 as well as PD-L1 expression via PI3K/AKT and NF-κB activation. It also induced PD-L1 inhibitor-resistance because CCL2 was expressed despite increased PD-L1, which was blocked by PD-L1 inhibitor. We also revealed that inhibition of TG2, instead of PD-L1, restored T cell-dependent killing effect by blocking expression of both PD-L1 and CCL2 in PD-L1(+) triple negative breast cancer (TNBC) cells. In addition, the TG2-expressing TNBC patient group showed higher PD-L1 expression incidence than did the TG2-negative TNBC patient group. In conclusion, TG2 induces primary PD-1/PD-L1 inhibitor-resistance by inducing CCL2 expression. TG2 blockade can be utilized as an excellent therapeutic strategy to overcome PD-L1 inhibitor-resistance in PD-L1(+) TNBC patients. Our study suggested that PD-L1 expression alone might not always be a predictive biomarker for PD-L1(+) TNBC, but TG2 could be a useful predictive marker to select PD-L1 inhibitor-resistant TNBC patients.
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Affiliation(s)
- Junyoung Choi
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
- Department of Biomedical Sciences, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Hee Jin Lee
- Department of Pathology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Shinkyo Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Hyun-Min Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
- Department of Biomedical Sciences, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Eunjin Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
- Department of Biomedical Sciences, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Yujin Jo
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Seyoung Seo
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Deokhoon Kim
- Center for Cancer Genome Discovery, Asan Institute for Life Science, Asan Medical CenterSeoul 05505, Republic of Korea
| | - Chang Hoon Lee
- Bio & Drug Discovery Division, Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology (KRICT)Daejeon, Republic of Korea
| | - Wanlim Kim
- Department of Orthopaedic Surgery, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Joo Young Ha
- Division of Hematology/Medical Oncology, Department of Internal Medicine, Chung-Ang University College of MedicineSeoul 06973, Republic of Korea
| | - Soo-Youl Kim
- Tumor Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer CenterGoyang 10408, Republic of Korea
| | - Gyungyub Gong
- Department of Pathology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Kyung Hae Jung
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Sook Ryun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Sang-We Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Kang-Seo Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
- Department of Biomedical Sciences, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
| | - Dae Ho Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of MedicineSeoul 05505, Republic of Korea
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Relationship between IL10 and PD-L1 in Liver Hepatocellular Carcinoma Tissue and Cell Lines. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8910183. [PMID: 32724815 PMCID: PMC7381951 DOI: 10.1155/2020/8910183] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 06/26/2020] [Indexed: 12/14/2022]
Abstract
Background Despite the large-scale clinical application of programmed death-ligand 1 (PD-L1) monoclonal antibody, reduction in its clinical response rate has become a gradual problem. As such, use of PD-L1 monoclonal antibody in combination with other anticarcinoma drugs has been the main strategy in improving its efficacy. Interleukin 10 (IL10) is a recognized inflammatory and immunosuppressive factor. Previous studies have suggested that there is a link between PD-L1 and IL10. Objective This study was aimed at clarifying the relationship between PD-L1 and IL10 in liver hepatocellular carcinoma (LIHC) and whether IL10 enhances the efficacy of PD-L1 inhibitor. Methods Expression levels of PD-L1 and IL10 in carcinoma and adjacent tissues were tested by immunochemistry, Western blotting, and RT-PCR. Survival duration and follow-up data of each patient were recorded. LIHC cell lines Bel7405 and MHCC 97-H were used for in vitro experiments. Exogenous IL10 and anti-IL10 were added to cell supernatant. Expression level of PD-L1 in the LIHC cell lines was determined using Western blotting and ELISA. CCK8 and transwell assays were adopted to examine the effect of PD-L1 combined with IL10 on proliferation, invasion, and metastasis of LIHC cells. Results The survival period of patients with low expression of IL10 was longer than that of patients with high expression (P = 0.01). Overexpression of PD-L1 increased the IL10 and Met levels in LIHC tissues and cell lines. IL10 downregulated the expression level of PD-L1 and enhanced the efficacy of crizotinib via the Met signaling pathway in the LIHC cells. Conclusions A combination of IL10 and PD-L1 inhibitor holds great promise as an effective treatment for LIHC.
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Frank GA, Kuznetsova OA, Zavalishina LE, Andreeva YY, Karaseva VV, Tyulyandin SA. [The first experience of PD-L1 testing of triple negative breast cancer with marker SP142 in Russia]. Arkh Patol 2020; 82:5-12. [PMID: 32593260 DOI: 10.17116/patol2020820315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
AIM OF STUDY To evaluate the pecularities of PD-L1 expression in triple negative breast cancer (TNBC) in the Russian population. MATERIALS AND METHODS For 7 months, within a scientific study of the Russian Society of Clinical Oncology (RUSSCO), we determined the PD-L1 status of 58 patients with TNBC. In each case, an immunohistochemical study was performed in a closed Ventana Bench Mark Ultra automatic stainer using a closed protocol with rabbit monoclonal antibodies Ventana PD-L1 SP142 and Opti View DAB IHC Detection Kit with Opti View Amplification Kit. RESULTS Positive PD-L1 status in TNBC was detected in 37.93% of cases. Almost all tumors had an expression level of up to 10%. Only 5.17% of cases showed ligand expression on tumor cells. CONCLUSIONS According to the results of the first experience of testing PD-L1 in TNLM in Russia, it was possible to obtain data comparable to the same data of large international studies. RUSSCO's information and logistic support allows making this analysis available to all citizens of the country.
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Affiliation(s)
- G A Frank
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | - O A Kuznetsova
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | - L E Zavalishina
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | - Yu Yu Andreeva
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | - V V Karaseva
- Russian National Research Medical University named after N.I. Pirogov, Moscow, Russia
| | - S A Tyulyandin
- National Medical Research Center for Oncology named after N. N. Blokhin, Moscow, Russia
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Kothari C, Osseni MA, Agbo L, Ouellette G, Déraspe M, Laviolette F, Corbeil J, Lambert JP, Diorio C, Durocher F. Machine learning analysis identifies genes differentiating triple negative breast cancers. Sci Rep 2020; 10:10464. [PMID: 32591639 PMCID: PMC7320018 DOI: 10.1038/s41598-020-67525-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023] Open
Abstract
Triple negative breast cancer (TNBC) is one of the most aggressive form of breast cancer (BC) with the highest mortality due to high rate of relapse, resistance, and lack of an effective treatment. Various molecular approaches have been used to target TNBC but with little success. Here, using machine learning algorithms, we analyzed the available BC data from the Cancer Genome Atlas Network (TCGA) and have identified two potential genes, TBC1D9 (TBC1 domain family member 9) and MFGE8 (Milk Fat Globule-EGF Factor 8 Protein), that could successfully differentiate TNBC from non-TNBC, irrespective of their heterogeneity. TBC1D9 is under-expressed in TNBC as compared to non-TNBC patients, while MFGE8 is over-expressed. Overexpression of TBC1D9 has a better prognosis whereas overexpression of MFGE8 correlates with a poor prognosis. Protein-protein interaction analysis by affinity purification mass spectrometry (AP-MS) and proximity biotinylation (BioID) experiments identified a role for TBC1D9 in maintaining cellular integrity, whereas MFGE8 would be involved in various tumor survival processes. These promising genes could serve as biomarkers for TNBC and deserve further investigation as they have the potential to be developed as therapeutic targets for TNBC.
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Affiliation(s)
- Charu Kothari
- Département de Médecine Moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada
- Centre de Recherche Sur Le Cancer, Centre de Recherche du CHU de Québec-Université Laval, 2705 Laurier Blvd, Bloc R4778, Québec, G1V4G2, Canada
| | - Mazid Abiodoun Osseni
- Département de Médecine Moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada
- Big Data Research Centre, CHU de Québec-Université Laval, Quebec City, QC, Canada
| | - Lynda Agbo
- Département de Médecine Moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada
- Centre de Recherche Sur Le Cancer, Centre de Recherche du CHU de Québec-Université Laval, 2705 Laurier Blvd, Bloc R4778, Québec, G1V4G2, Canada
| | - Geneviève Ouellette
- Département de Médecine Moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada
- Centre de Recherche Sur Le Cancer, Centre de Recherche du CHU de Québec-Université Laval, 2705 Laurier Blvd, Bloc R4778, Québec, G1V4G2, Canada
| | - Maxime Déraspe
- Département de Médecine Moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada
- Big Data Research Centre, CHU de Québec-Université Laval, Quebec City, QC, Canada
| | - François Laviolette
- Big Data Research Centre, CHU de Québec-Université Laval, Quebec City, QC, Canada
- Département D'informatique Et de génie Logiciel, Faculté des sciences et de génie, Université Laval, Québec City, QC, Canada
| | - Jacques Corbeil
- Département de Médecine Moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada
- Big Data Research Centre, CHU de Québec-Université Laval, Quebec City, QC, Canada
| | - Jean-Philippe Lambert
- Département de Médecine Moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada
- Centre de Recherche Sur Le Cancer, Centre de Recherche du CHU de Québec-Université Laval, 2705 Laurier Blvd, Bloc R4778, Québec, G1V4G2, Canada
| | - Caroline Diorio
- Centre de Recherche Sur Le Cancer, Centre de Recherche du CHU de Québec-Université Laval, 2705 Laurier Blvd, Bloc R4778, Québec, G1V4G2, Canada
- Département de Médecine Sociale Et Préventive, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - Francine Durocher
- Département de Médecine Moléculaire, Faculté de médecine, Université Laval, Québec City, QC, Canada.
- Centre de Recherche Sur Le Cancer, Centre de Recherche du CHU de Québec-Université Laval, 2705 Laurier Blvd, Bloc R4778, Québec, G1V4G2, Canada.
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Guo H, Ding Q, Gong Y, Gilcrease MZ, Zhao M, Zhao J, Sui D, Wu Y, Chen H, Liu H, Zhang J, Resetkova E, Moulder SL, Wang WL, Huo L. Comparison of three scoring methods using the FDA-approved 22C3 immunohistochemistry assay to evaluate PD-L1 expression in breast cancer and their association with clinicopathologic factors. Breast Cancer Res 2020; 22:69. [PMID: 32576238 PMCID: PMC7310491 DOI: 10.1186/s13058-020-01303-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 06/01/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND In the evaluation of PD-L1 expression to select patients for anti-PD-1/PD-L1 treatment, uniform guidelines that account for different immunohistochemistry assays, different cell types and different cutoff values across tumor types are lacking. Data on how different scoring methods compare in breast cancer are scant. METHODS Using FDA-approved 22C3 diagnostic immunohistochemistry assay, we retrospectively evaluated PD-L1 expression in 496 primary invasive breast tumors that were not exposed to anti-PD-1/PD-L1 treatment and compared three scoring methods (TC: invasive tumor cells; IC: tumor-infiltrating immune cells; TCIC: a combination of tumor cells and immune cells) in expression frequency and association with clinicopathologic factors. RESULTS In the entire cohort, positive PD-L1 expression was observed in 20% of patients by TCIC, 16% by IC, and 10% by TC, with a concordance of 87% between the three methods. In the triple-negative breast cancer patients, positive PD-L1 expression was observed in 35% by TCIC, 31% by IC, and 16% by TC, with a concordance of 76%. Associations between PD-L1 and clinicopathologic factors were investigated according to receptor groups and whether the patients had received neoadjuvant chemotherapy. The three scoring methods showed differences in their associations with clinicopathologic factors in all subgroups studied. Positive PD-L1 expression by IC was significantly associated with worse overall survival in patients with neoadjuvant chemotherapy and showed a trend for worse overall survival and distant metastasis-free survival in triple-negative patients with neoadjuvant chemotherapy. Positive PD-L1 expression by TCIC and TC also showed trends for worse survival in different subgroups. CONCLUSIONS Our findings indicate that the three scoring methods with a 1% cutoff are different in their sensitivity for PD-L1 expression and their associations with clinicopathologic factors. Scoring by TCIC is the most sensitive way to identify PD-L1-positive breast cancer by immunohistochemistry. As a prognostic marker, our study suggests that PD-L1 is associated with worse clinical outcome, most often shown by the IC score; however, the other scores may also have clinical implications in some subgroups. Large clinical trials are needed to test the similarities and differences of these scoring methods for their predictive values in anti-PD-1/PD-L1 therapy.
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Affiliation(s)
- Hua Guo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Qingqing Ding
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Yun Gong
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Michael Z Gilcrease
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Min Zhao
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Jun Zhao
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Dawen Sui
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun Wu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Hui Chen
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Hui Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Jinxia Zhang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Erika Resetkova
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Stacy L Moulder
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wei-Lien Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Lei Huo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Unit 85, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
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Wu X, Li F, Li Y, Yu Y, Liang C, Zhang B, Zhao C, Lu A, Zhang G. A PD-L1 Aptamer Selected by Loss-Gain Cell-SELEX Conjugated with Paclitaxel for Treating Triple-Negative Breast Cancer. Med Sci Monit 2020; 26:e925583. [PMID: 32574155 PMCID: PMC7331476 DOI: 10.12659/msm.925583] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/02/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The clinical challenges of triple-negative breast cancer (TNBC) includes the lack of targeted therapy and chemoresistance. TNBC has relatively high PD-L1 expression, and PD-L1 antibody in combination with nab-paclitaxel has been approved by FDA for TNBC treatment. Aptamers, also termed chemical antibody, are widely used in targeted drug delivery. The present study aimed to select a DNA aptamer that could specifically bind and deliver drugs to TNBC cells. MATERIAL AND METHODS An innovative loss-gain cell-SELEX strategy was used to select DNA aptamer for PD-L1 protein. Construction of PD-L1 knock-out and over-expression MDA-MB-231 cell lines were conducted through transfection and confirmed by western blot and flow cytometry. Confocal microscopy and flow cytometry were used to analyze the binding ability of aptamer with TNBC cells. The cytotoxicity of aptamer-paclitaxel complex against TNBC cells was evaluated by Cell Counting Kit-8 assay. The reactivation of the T cell function by aptamer was measured by IL-2 enzyme-linked immunosorbent assay after T cells co-cultured with tumor cells. RESULTS In this work, using an innovative loss-gain cell-SELEX strategy, we screened a PD-L1-targeting aptamer. PD-L1 aptamer selectively bound to PD-L1 over-expressed TNBC cells with a dissociation constant in the nanomolar range. PD-L1 aptamer could also inhibit PD-1/PD-L1 interaction and restore the function of T cells. Moreover, we developed a PD-L1 aptamer-paclitaxel conjugate which showed improved cellular uptake and anti-proliferation efficacy in PD-L1 over-expressed TNBC cells. CONCLUSIONS In summary, these findings suggest that the selected PD-L1 aptamer might have potential implication in immune modulation and targeted therapy against TNBC.
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Affiliation(s)
- Xiaoqiu Wu
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, Guangdong, P.R. China
| | - Fangfei Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, Guangdong, P.R. China
| | - Yongshu Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
| | - Yuanyuan Yu
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, Guangdong, P.R. China
| | - Chao Liang
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, Guangdong, P.R. China
| | - Baoting Zhang
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
| | - Chuanzong Zhao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
- Key Laboratory for Experimental Teratology of The Ministry of Education and Department of Pathology, School of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Aiping Lu
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, Guangdong, P.R. China
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, P.R. China
- Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, P.R. China
| | - Ge Zhang
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P.R. China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, Guangdong, P.R. China
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Zheng X, Fernando V, Sharma V, Walia Y, Letson J, Furuta S. Correction of arginine metabolism with sepiapterin-the precursor of nitric oxide synthase cofactor BH 4-induces immunostimulatory-shift of breast cancer. Biochem Pharmacol 2020; 176:113887. [PMID: 32112882 PMCID: PMC7842273 DOI: 10.1016/j.bcp.2020.113887] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 02/24/2020] [Indexed: 02/07/2023]
Abstract
Immunotherapy is a first-line treatment for many tumor types. However, most breast tumors are immuno-suppressive and only modestly respond to immunotherapy. We hypothesized that correcting arginine metabolism might improve the immunogenicity of breast tumors. We tested whether supplementing sepiapterin, the precursor of tetrahydrobiopterin (BH4)-the nitric oxide synthase (NOS) cofactor-redirects arginine metabolism from the pathway synthesizing polyamines to that of synthesizing nitric oxide (NO) and make breast tumors more immunogenic. We showed that sepiapterin elevated NO but lowered polyamine levels in tumor cells, as well as in tumor-associated macrophages (TAMs). This not only suppressed tumor cell proliferation, but also induced the conversion of TAMs from the immuno-suppressive M2-type to immuno-stimulatory M1-type. Furthermore, sepiapterin abrogated the expression of a checkpoint ligand, PD-L1, in tumors in a STAT3-dependent manner. This is the first study which reveals that supplementing sepiapterin normalizes arginine metabolism, improves the immunogenicity and inhibits the growth of breast tumor cells.
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Affiliation(s)
- Xunzhen Zheng
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH 43614, USA
| | - Veani Fernando
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH 43614, USA
| | - Vandana Sharma
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH 43614, USA
| | - Yashna Walia
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH 43614, USA
| | - Joshua Letson
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH 43614, USA
| | - Saori Furuta
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave., Toledo, OH 43614, USA.
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