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Safaei S, Yari A, Pourbagherian O, Maleki LA. The role of cytokines in shaping the future of Cancer immunotherapy. Cytokine 2025; 189:156888. [PMID: 40010034 DOI: 10.1016/j.cyto.2025.156888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/13/2025] [Accepted: 02/05/2025] [Indexed: 02/28/2025]
Abstract
As essential immune system regulators, cytokines are essential for modulating both innate and adaptive immunological responses. They have become important tools in cancer immunotherapy, improving the immune system's capacity to identify and destroy tumor cells. This article examines the background, workings, and therapeutic uses of cytokines, such as interleukins, interferons, and granulocyte-macropHage colony-stimulating factors, in the management of cancer. It examines the many ways that cytokines affect immune cell activation, signaling pathways, tumor development, metastasis, and prognosis by modifying the tumor microenvironment. Despite the limited effectiveness of cytokine-based monotherapy, recent developments have concentrated on new fusion molecules such as immunocytokines, cytokine delivery improvements, and combination techniques to maximize treatment efficacy while reducing adverse effects. Current FDA-approved cytokine therapeutics and clinical trial results are also included in this study, which offers insights into how cytokines might be used with other therapies including checkpoint inhibitors, chemotherapy, and radiation therapy to address cancer treatment obstacles. This study addresses the intricacies of cytokine interactions in the tumor microenvironment, highlighting the possibility for innovative treatment methods and suggesting fresh techniques for enhancing cytokine-based immunotherapies. PEGylation, viral vector-mediated cytokine gene transfer, antibody-cytokine fusion proteins (immunocytokines), and other innovative cytokine delivery techniques are among the novelties of this work, which focuses on the most recent developments in cytokine-based immunotherapy. Additionally, the study offers a thorough examination of the little-reviewed topic of cytokine usage in conjunction with other treatment techniques. It also discusses the most recent clinical studies and FDA-approved therapies, providing a modern perspective on the developing field of cancer immunotherapy and suggesting creative ways to improve treatment effectiveness while lowering toxicity. BACKGROUND: Cytokines are crucial in cancer immunotherapy for regulating immune responses and modifying the tumor microenvironment (TME). However, challenges with efficacy and safety have driven research into advanced delivery methods and combination therapies to enhance their therapeutic potential.
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Affiliation(s)
- Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - AmirHossein Yari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Omid Pourbagherian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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2
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Ziogou A, Giannakodimos A, Giannakodimos I, Schizas D, Charalampakis N. Effect of Helicobacter Pylori infection on immunotherapy for gastrointestinal cancer: a narrative review. Immunotherapy 2025; 17:355-368. [PMID: 40087147 PMCID: PMC12045566 DOI: 10.1080/1750743x.2025.2479410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 03/11/2025] [Indexed: 03/16/2025] Open
Abstract
Immunotherapy for gastrointestinal cancers has elicited considerable amount of attention as a viable therapeutic option for several cancer types. Gut microbiome as a whole plays a critical role in shaping immune responses and influencing cancer progression. Recent evidence suggests that Helicobacter pylori (H. pylori), may influence immunotherapy efficacy by modulating the tumor microenvironment. Infection with H. pylori is common as it affects approximately 50% of the global population and remains the leading risk factor for gastric cancer. Interestingly, recent clinical and preclinical data has associated H. pylori with colorectal cancer carcinogenesis. Gut microbiome appears to be a modulator of the relationship between the immune system, gastrointestinal cancer development and existing therapies. Infection with H. pylori may affect immunotherapy results in both gastroesophageal and colorectal cancer; favorable results were noticed in H. pylori positive patients with gastric cancer, while in colorectal cancer patients the pathogen seemed to impede immunotherapy's action. This article aims to review current data on the role of H. pylori in triggering gastric inflammation and cancer, as well as its potential involvement in colorectal cancer development. Additionally, it seeks to highlight the impact of H. pylori infection on the response to immunotherapy in gastrointestinal cancers.
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Affiliation(s)
- Afroditi Ziogou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, Greece
| | | | - Ilias Giannakodimos
- Departement of Urology, Attikon University Hospital of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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3
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Bettinsoli V, Melzi G, Marchese I, Pantaleoni S, Passoni FC, Corsini E. New approach methodologies to assess wanted and unwanted drugs-induced immunostimulation. Curr Res Toxicol 2025; 8:100222. [PMID: 40027547 PMCID: PMC11872130 DOI: 10.1016/j.crtox.2025.100222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 01/16/2025] [Accepted: 01/28/2025] [Indexed: 03/05/2025] Open
Abstract
This review examines various classes of drugs, focusing on their therapeutic and adverse effects, particularly in relation to immunostimulation. We emphasize the potential of new approach methodologies (NAMs) to study both expected and unexpected immunostimulatory effects. By evaluating the modes of action of different immunostimulatory drugs, we aim to provide insights into effectively assessing unwanted immunostimulatory responses. The review begins by exploring drugs that stimulate the immune system-including immunostimulants, monoclonal antibodies, chemotherapeutics, and nucleic acid-based drugs-to outline NAMs that could be employed to evaluate immunostimulation.
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Affiliation(s)
- Valeria Bettinsoli
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9 20133 Milan, Italy
- Department of Pharmacy, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Gloria Melzi
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9 20133 Milan, Italy
| | - Irene Marchese
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9 20133 Milan, Italy
| | - Sofia Pantaleoni
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9 20133 Milan, Italy
| | - Francesca Carlotta Passoni
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9 20133 Milan, Italy
| | - Emanuela Corsini
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9 20133 Milan, Italy
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4
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Koppers MJA, Monnikhof M, Meeldijk J, Koorman T, Bovenschen N. Chimeric antigen receptor-macrophages: Emerging next-generation cell therapy for brain cancer. Neurooncol Adv 2025; 7:vdaf059. [PMID: 40376682 PMCID: PMC12080554 DOI: 10.1093/noajnl/vdaf059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025] Open
Abstract
Adoptive cell-based therapy utilizing chimeric antigen receptor (CAR)-T technology holds promise in the field of neuro-oncology. Significant progress has been made in enhancing both the efficacy and safety of CAR-T-cell therapies. However, challenges such as the multifaceted immunosuppressive impact of the tumor microenvironment and insufficient CAR-T-cell infiltration into brain tumor sites remain a major hurdles. Emerging novel approaches utilizing CAR-macrophages (CAR-MACs) show potent results for brain tumor immunotherapy. CAR-MACs localize to tumor sites more readily, increase immune cell infiltrates, and demonstrate high antitumor efficacy by effectively eliminating tumor cells through mechanisms such as phagocytosis or efferocytosis. This review discusses the current advancements in CAR-MAC cell therapies for brain cancer, followed by an overview of research on manufacturing CAR-MACs for clinical application. We further highlight the potential future applications of CAR-MACs in combinatory therapies in the treatment of brain tumors.
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Affiliation(s)
- Myrthe J A Koppers
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Matthijs Monnikhof
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jan Meeldijk
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Thijs Koorman
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Niels Bovenschen
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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Yi M, Li T, Niu M, Zhang H, Wu Y, Wu K, Dai Z. Targeting cytokine and chemokine signaling pathways for cancer therapy. Signal Transduct Target Ther 2024; 9:176. [PMID: 39034318 PMCID: PMC11275440 DOI: 10.1038/s41392-024-01868-3] [Citation(s) in RCA: 64] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/30/2024] [Accepted: 05/11/2024] [Indexed: 07/23/2024] Open
Abstract
Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.
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Affiliation(s)
- Ming Yi
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, People's Republic of China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Haoxiang Zhang
- Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, 350001, People's Republic of China
| | - Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Zhijun Dai
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, People's Republic of China.
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6
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Campia G, Beltrán-Visiedo M, Soler-Agesta R, Sato A, Bloy N, Zhao L, Liu P, Kepp O, Kroemer G, Galluzzi L, Galassi C. Flow cytometry-assisted analysis of phenotypic maturation markers on an immortalized dendritic cell line. Methods Cell Biol 2024; 189:153-168. [PMID: 39393881 DOI: 10.1016/bs.mcb.2024.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2024]
Abstract
Dendritic cells (DCs), and especially so conventional type I DCs (cDC1s), are fundamental regulators of anticancer immunity, largely reflecting their superior ability to engulf tumor-derived material and process it for cross-presentation on MHC Class I molecules to CD8+ cytotoxic T lymphocytes (CTLs). Thus, investigating key DC functions including (but not limited to) phagocytic capacity, expression of CTL-activating ligands on the cell surface, and cross-presentation efficacy is an important component of multiple immuno-oncology studies. Unfortunately, DCs are terminally differentiated cells, implying that they cannot be propagated indefinitely in vitro and hence must be generated ad hoc from circulating or bone marrow-derived precursors, which presents several limitations. Here, we propose a simple, cytofluorometric method to quantify phenotypic activation markers including CD80, CD86 and MHC class II molecules on the surface of a conditionally immortalized immature DC line that can be indefinitely propagated in vitro but also driven into maturation at will with a simple change in culture conditions. Upon appropriate scaling and automatization, this approach is compatible with high-throughput screening programs for the discovery of novel DC activators that do not suffer from batch variability and other limitations associated with the generation of fresh DCs.
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Affiliation(s)
- Ginevra Campia
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States
| | - Manuel Beltrán-Visiedo
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States
| | - Ruth Soler-Agesta
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States; University of Zaragoza/Aragón Health Research Institute, Biochemistry and Molecular and Cell Biology, Zaragoza, Spain
| | - Ai Sato
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States
| | - Norma Bloy
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States
| | - Liwei Zhao
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, Université Paris Saclay, Villejuif, France
| | - Peng Liu
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, Université Paris Saclay, Villejuif, France
| | - Oliver Kepp
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, Université Paris Saclay, Villejuif, France
| | - Guido Kroemer
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, Université Paris Saclay, Villejuif, France; Pôle de Biologie, Hôpital européen Georges Pompidou, AP-HP, Paris, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States; Sandra and Edward Meyer Cancer Center, New York, NY, United States; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, United States.
| | - Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States.
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7
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Barisas DAG, Choi K. Extramedullary hematopoiesis in cancer. Exp Mol Med 2024; 56:549-558. [PMID: 38443597 PMCID: PMC10985111 DOI: 10.1038/s12276-024-01192-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/21/2023] [Accepted: 12/26/2023] [Indexed: 03/07/2024] Open
Abstract
Hematopoiesis can occur outside of the bone marrow during inflammatory stress to increase the production of primarily myeloid cells at extramedullary sites; this process is known as extramedullary hematopoiesis (EMH). As observed in a broad range of hematologic and nonhematologic diseases, EMH is now recognized for its important contributions to solid tumor pathology and prognosis. To initiate EMH, hematopoietic stem cells (HSCs) are mobilized from the bone marrow into the circulation and to extramedullary sites such as the spleen and liver. At these sites, HSCs primarily produce a pathological subset of myeloid cells that contributes to tumor pathology. The EMH HSC niche, which is distinct from the bone marrow HSC niche, is beginning to be characterized. The important cytokines that likely contribute to initiating and maintaining the EMH niche are KIT ligands, CXCL12, G-CSF, IL-1 family members, LIF, TNFα, and CXCR2. Further study of the role of EMH may offer valuable insights into emergency hematopoiesis and therapeutic approaches against cancer. Exciting future directions for the study of EMH include identifying common and distinct EMH mechanisms in cancer, infectious diseases, and chronic autoimmune diseases to control these conditions.
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Affiliation(s)
- Derek A G Barisas
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Kyunghee Choi
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
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Sun X, Watanabe T, Oda Y, Shen W, Ahmad A, Ouda R, de Figueiredo P, Kitamura H, Tanaka S, Kobayashi KS. Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I. Proc Natl Acad Sci U S A 2024; 121:e2310821121. [PMID: 38300873 PMCID: PMC10861931 DOI: 10.1073/pnas.2310821121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 12/30/2023] [Indexed: 02/03/2024] Open
Abstract
Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the low level of MHC class I is associated with poor prognosis and resistance to checkpoint blockade therapies. However, there is lmited approaches to specifically induce MHC class I to date. Here, we show an approach for robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA)/NLRC5, using a CRISPR/Cas9-based gene-specific system, designated TRED-I (Targeted reactivation and demethylation for MHC-I). The TRED-I system specifically recruits a demethylating enzyme and transcriptional activators on the NLRC5 promoter, driving increased MHC class I antigen presentation and accelerated CD8+ T cell activation. Introduction of the TRED-I system in an animal cancer model exhibited tumor-suppressive effects accompanied with increased infiltration and activation of CD8+ T cells. Moreover, this approach boosted the efficacy of checkpoint blockade therapy using anti-PD1 (programmed cell death protein) antibody. Therefore, targeting NLRC5 by this strategy provides an attractive therapeutic approach for cancer.
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Affiliation(s)
- Xin Sun
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Toshiyuki Watanabe
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Yoshitaka Oda
- Department of Cancer Pathology, Graduate School of Medicine, Hokkaido University, Hokkaido, Sapporo060-8638, Japan
| | - Weidong Shen
- Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Alaa Ahmad
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Ryota Ouda
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
| | - Paul de Figueiredo
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX77807
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO65211
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO65211
- Department of Veterinary Pathobiology, University of MissouriSchool of Veterinary Medicine, Columbia, MO65211
| | - Hidemitsu Kitamura
- Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo060-8638, Japan
- Department of Biomedical Engineering, Faculty of Science and Engineering, Toyo University, Kawagoe350-8585, Japan
| | - Shinya Tanaka
- Department of Cancer Pathology, Graduate School of Medicine, Hokkaido University, Hokkaido, Sapporo060-8638, Japan
- Institute for Chemical Reaction Design and Discovery, Hokkaido University, Sapporo001-0021, Japan
| | - Koichi S. Kobayashi
- Department of Immunology, Graduate School of Medicine, Hokkaido University, Sapporo060-8638, Japan
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX77807
- Institute for Vaccine Research and Development, Hokkaido University, Sapporo060-8638, Japan
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9
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Rastin F, Javid H, Oryani MA, Rezagholinejad N, Afshari AR, Karimi-Shahri M. Immunotherapy for colorectal cancer: Rational strategies and novel therapeutic progress. Int Immunopharmacol 2024; 126:111055. [PMID: 37992445 DOI: 10.1016/j.intimp.2023.111055] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 09/30/2023] [Accepted: 10/09/2023] [Indexed: 11/24/2023]
Abstract
There are increasing incidences and mortality rates for colorectal cancer in the world. It is common for chemotherapy and radiation given to patients with colorectal cancer to cause toxicities that limit their effectiveness and cause cancer cells to become resistant to these treatments. Additional targeted treatments are needed to improve patient's quality of life and outcomes. Immunotherapy has rapidly emerged as an incredibly exciting and promising avenue for cancer treatment in recent years. This innovative approach provides novel options for tackling solid tumors, effectively establishing itself as a new cornerstone in cancer treatment. Specifically, in the realm of colorectal cancer (CRC), there is great promise in developing new drugs that target immune checkpoints, offering a hopeful and potentially transformative solution. While immunotherapy of CRC has made significant advances, there are still obstacles and limitations. CRC patients have a poor response to treatment because of the immune-suppressing function of their tumor microenvironment (TME). In addition to blocking inhibitory immune checkpoints, checkpoint-blocking antibodies may also boost immune responses against tumors. The review summarizes recent advances in immune checkpoint inhibitors (ICIs) for CRC, including CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3.
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Affiliation(s)
- Farangis Rastin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahsa Akbari Oryani
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Amir-R Afshari
- Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran.
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10
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Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
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Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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11
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Mazzio E, Barnes A, Badisa R, Council S, Soliman KFA. Plants against cancer: the immune-boosting herbal microbiome: not of the plant, but in the plant. Basic concepts, introduction, and future resource for vaccine adjuvant discovery. Front Oncol 2023; 13:1180084. [PMID: 37588095 PMCID: PMC10426289 DOI: 10.3389/fonc.2023.1180084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/30/2023] [Indexed: 08/18/2023] Open
Abstract
The presence of microorganism communities (MOCs) comprised of bacteria, fungi, archaea, algae, protozoa, viruses, and the like, are ubiquitous in all living tissue, including plant and animal. MOCs play a significant role in establishing innate and acquired immunity, thereby influencing susceptibility and resistance to disease. This understanding has fostered substantial advancements in several fields such as agriculture, food science/safety, and the development of vaccines/adjuvants, which rely on administering inactivated-attenuated MOC pathogens. Historical evidence dating back to the 1800s, including reports by Drs Busch, Coley, and Fehleisen, suggested that acute febrile infection in response to "specific microbes" could trigger spontaneous tumor remission in humans. This discovery led to the purposeful administration of the same attenuated strains, known as "Coley's toxin," marking the onset of the first microbial (pathogen) associated molecular pattern (MAMPs or PAMPs)-based tumor immunotherapy, used clinically for over four decades. Today, these same MAMPS are consumed orally by billions of consumers around the globe, through "specific" mediums (immune boosting "herbal supplements") as carriers of highly concentrated MOCs accrued in roots, barks, hulls, sea algae, and seeds. The American Herbal Products Association (AHPA) mandates microbial reduction in botanical product processing but does not necessitate the removal of dead MAMP laden microbial debris, which we ingest. Moreover, while existing research has focused on the immune-modulating role of plant phytochemicals, the actual immune-boosting properties might instead reside solely in the plant's MOC MAMP laden biomass. This assertion is logical, considering that antigenic immune-provoking epitopes, not phytochemicals, are known to stimulate immune response. This review explores a neglected area of research regarding the immune-boosting effects of the herbal microbiome - a presence which is indirectly corroborated by various peripheral fields of study and poses a fundamental question: Given that food safety focuses on the elimination of harmful pathogens and crop science acknowledges the existence of plant microbiomes, what precisely are the immune effects of ingesting MAMPs of diverse structural composition and concentration, and where are these distributed in our botanicals? We will discuss the topic of concentrated edible MAMPs as acid and thermally stable motifs found in specific herbs and how these would activate cognate pattern recognition receptors (PPRs) in the upper gut-associated lymphoid tissue (GALT), including Peyer's patches and the lamina propria, to boost antibody titers, CD8+ and CD4+ T cells, NK activity, hematopoiesis, and facilitating M2 to M1 macrophage phenotype transition in a similar manner as vaccines. This new knowledge could pave the way for developing bioreactor-grown/heat-inactivated MOC therapies to boost human immunity against infections and improve tumor surveillance.
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Affiliation(s)
- Elizabeth Mazzio
- Divison of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A & M University, Tallahassee, FL, United States
| | - Andrew Barnes
- Divison of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A & M University, Tallahassee, FL, United States
| | - Ramesh Badisa
- Divison of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A & M University, Tallahassee, FL, United States
| | - Stevie Council
- John Gnabre Science Research Institute, Baltimore, MD, United States
| | - Karam F. A. Soliman
- Divison of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A & M University, Tallahassee, FL, United States
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12
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Liu JL, Yang M, Bai JG, Liu Z, Wang XS. "Cold" colorectal cancer faces a bottleneck in immunotherapy. World J Gastrointest Oncol 2023; 15:240-250. [PMID: 36908324 PMCID: PMC9994051 DOI: 10.4251/wjgo.v15.i2.240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/18/2022] [Accepted: 01/05/2023] [Indexed: 02/14/2023] Open
Abstract
The advent of immunotherapy and the development of immune checkpoint inhibitors (ICIs) are changing the way we think about cancer treatment. ICIs have shown clinical benefits in a variety of tumor types, and ICI-based immunotherapy has shown effective clinical outcomes in immunologically "hot" tumors. However, for immunologically "cold" tumors such as colorectal cancer (CRC), only a limited number of patients are currently benefiting from ICIs due to limitations such as individual differences and low response rates. In this review, we discuss the classification and differences between hot and cold CRC and the current status of research on cold CRC, and summarize the treatment strategies and challenges of immunotherapy for cold CRC. We also explain the mechanism, biology, and role of immunotherapy for cold CRC, which will help clarify the future development of immunotherapy for cold CRC and discovery of more emerging strategies for the treatment of cold CRC.
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Affiliation(s)
- Jia-Liang Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
| | - Ming Yang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
| | - Jun-Ge Bai
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
| | - Zheng Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
| | - Xi-Shan Wang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
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13
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Bhattacharjee R, Das D, Bhadhuri R, Chakraborty S, Dey T, Buragohain R, Nath A, Muduli K, Barman P, Gundamaraju R. Cellular Landscaping of COVID-19 and Gynaecological Cancers: An Infrequent Correlation. JOURNAL OF ONCOLOGY 2022; 2022:5231022. [PMID: 36299504 PMCID: PMC9592241 DOI: 10.1155/2022/5231022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 07/16/2022] [Indexed: 01/08/2023]
Abstract
COVID-19 resulted in a mortality rate of 3-6% caused by SARS-CoV-2 and its variant leading to unprecedented consequences of acute respiratory distress septic shock and multiorgan failure. In such a situation, evaluation, diagnosis, treatment, and care for cancer patients are difficult tasks faced by medical staff. Moreover, patients with gynaecological cancer appear to be more prone to severe infection and mortality from COVID-19 due to immunosuppression by chemotherapy and coexisting medical disorders. To deal with such a circumtances oncologists have been obliged to reconsider the entire diagnostic, treatment, and management approach. This review will provide and discuss the molecular link with gynaecological cancer under COVID-19 infection, providing a novel bilateral relationship between the two infections. Moreover, the authors have provided insights to discuss the pathobiology of COVID-19 in gynaecological cancer and their risks associated with such comorbidity. Furthermore, we have depicted the overall impact of host immunity along with guidelines for the treatment of patients with gynaecological cancer under COVID-19 infection. We have also discussed the feasible scope for the management of COVID-19 and gynaecological cancer.
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Affiliation(s)
- Rahul Bhattacharjee
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Debanjan Das
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | | | | | - Tanima Dey
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Rupam Buragohain
- Department of Biotechnology, Gauhati UNiversity, Gopinath Bordoloi Nagar, Guwahati 781014, Assam, India
| | - Asim Nath
- Department of Biotechnology, Gauhati UNiversity, Gopinath Bordoloi Nagar, Guwahati 781014, Assam, India
| | - Kartik Muduli
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Pranjan Barman
- Department of Biotechnology, Gauhati UNiversity, Gopinath Bordoloi Nagar, Guwahati 781014, Assam, India
| | - Rohit Gundamaraju
- ER Stress and Mucosal Immunology Lab, School of Health Sciences, University of Tasmania, Launceston, Tasmania, Australia
- Division of Gastroenterology, School of Medicine, Washington University at St Louis, St Louis, MO, USA
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14
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Xiong F, Wang Q, Wu GH, Liu WZ, Wang B, Chen YJ. Direct and indirect effects of IFN-α2b in malignancy treatment: not only an archer but also an arrow. Biomark Res 2022; 10:69. [PMID: 36104718 PMCID: PMC9472737 DOI: 10.1186/s40364-022-00415-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
Interferon-α2b (IFN-α2b) is a highly active cytokine that belongs to the interferon-α (IFN-α) family. IFN-α2b has beneficial antiviral, antitumour, antiparasitic and immunomodulatory activities. Direct and indirect antiproliferative effects of IFN-α2b have been found to occur via multiple pathways, mainly the JAK-STAT pathway, in certain cancers. This article reviews mechanistic studies and clinical trials on IFN-α2b. Potential regulators of the function of IFN-α2b were also reviewed, which could be utilized to relieve the poor response to IFN-α2b. IFN-α2b can function not only by enhancing the systematic immune response but also by directly killing tumour cells. Different parts of JAK-STAT pathway activated by IFN-α2b, such as interferon alpha and beta receptors (IFNARs), Janus kinases (JAKs) and IFN‐stimulated gene factor 3 (ISGF3), might serve as potential target for enhancing the pharmacological action of IFN-α2b. Despite some issues that remain to be solved, based on current evidence, IFN-α2b can inhibit disease progression and improve the survival of patients with certain types of malignant tumours. More efforts should be made to address potential adverse effects and complications.
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15
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Takenaka Y, Takemoto N, Otsuka T, Nishio M, Tanida M, Fujii T, Hayashi K, Suzuki M, Mori M, Yamamoto Y, Uno A, Inohara H. Predictive significance of body composition indices in patients with head and neck squamous cell carcinoma treated with nivolumab: A multicenter retrospective study. Oral Oncol 2022; 132:106018. [PMID: 35835055 DOI: 10.1016/j.oraloncology.2022.106018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 06/19/2022] [Accepted: 07/06/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND The identification of predictive factors is imperative for identifying patients with optimal responses to nivolumab. We aimed to determine whether body composition parameters can predict treatment outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with nivolumab. METHOD We performed a multicenter retrospective chart review of patients with recurrent and/or metastatic HNSCC treated with nivolumab between 2017 and 2020. Computed tomography images and anthropometric measures were used to determine the skeletal muscle index (SMI), subcutaneous adipose index, visceral adipose index (VAI), and body mass index. Objective response, overall survival (OS), progression-free survival (PFS), and severe immune-related adverse events (irAEs) were the main outcomes. Odds ratios (ORs) and hazard ratios (HRs) for low-index groups compared with high-index groups were calculated for these outcomes. RESULTS Our study comprised 114 patients with a median follow-up period of 23.1 months. Low SMI and low VAI were significantly associated with poor disease control [OR: 0.39, 95% confidence interval (CI): 0.15-0.97] and poor response (OR: 0.38, 95% CI: 0.15-0.94), respectively. Low SMI independently predicted poor OS (HR: 2.06, 95% CI: 1.16-3.67), poor PFS (HR: 1.74, 95% CI: 1.04-2.92), and increased incidence of irAEs (OR: 6.00, 95% CI: 1.04-34.61). Low VAI independently predicted poor PFS (HR 2.07, 95% CI: 1.15-3.73). CONCLUSION The SMI and VAI are predictive factors of nivolumab therapy in patients with HNSCC. Body composition indices should be assessed before nivolumab treatment for achieving optimal responses to nivolumab.
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Affiliation(s)
- Yukinori Takenaka
- Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan; Department of Otorhinolaryngology, Osaka Police Hospital, Japan.
| | - Norihiko Takemoto
- Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan
| | - Tomoyuki Otsuka
- Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan
| | - Minako Nishio
- Department of Medical Oncology, Osaka International Cancer Institute, Japan
| | - Masashi Tanida
- Department of Head and Neck Surgery, Osaka International Cancer Institute, Japan
| | - Takashi Fujii
- Department of Head and Neck Surgery, Osaka International Cancer Institute, Japan
| | - Kazuki Hayashi
- Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan
| | - Motoyuki Suzuki
- Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan
| | - Masashi Mori
- Department of Otorhinolaryngology-Head and Neck Surgery, Osaka General Medical Center, Japan
| | - Yoshifumi Yamamoto
- Department of Otorhinolaryngology-Head and Neck Surgery, Osaka General Medical Center, Japan
| | - Atsuhiko Uno
- Department of Otorhinolaryngology-Head and Neck Surgery, Osaka General Medical Center, Japan
| | - Hidenori Inohara
- Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Japan
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16
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Zhang Y, Cui Q, Xu M, Liu D, Yao S, Chen M. Current Advances in PD-1/PD-L1 Blockade in Recurrent Epithelial Ovarian Cancer. Front Immunol 2022; 13:901772. [PMID: 35833132 PMCID: PMC9271774 DOI: 10.3389/fimmu.2022.901772] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/30/2022] [Indexed: 12/24/2022] Open
Abstract
Immunotherapies have revolutionized the treatment of a variety of cancers. Epithelial ovarian cancer is the most lethal gynecologic malignancy, and the rate of advanced tumor progression or recurrence is as high as 80%. Current salvage strategies for patients with recurrent ovarian cancer are rarely curative. Recurrent ovarian cancer is a “cold tumor”, predominantly due to a lack of tumor antigens and an immunosuppressive tumor microenvironment. In trials testing programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) blockade as a monotherapy, the response rate was only 8.0-22.2%. In this review, we illustrate the status of cold tumors in ovarian cancer and summarize the existing clinical trials investigating PD-1/PD-L1 blockade in recurrent ovarian cancer. Increasing numbers of immunotherapy combination trials have been set up to improve the response rate of EOC. The current preclinical and clinical development of immunotherapy combination therapy to convert an immune cold tumor into a hot tumor and their underlying mechanisms are also reviewed. The combination of anti-PD-1/PD-L1 with other immunomodulatory drugs or therapies, such as chemotherapy, antiangiogenic therapies, poly (ADP-ribose) polymerase inhibitors, adoptive cell therapy, and oncolytic therapy, could be beneficial. Further efforts are merited to transfer these results to a broader clinical application.
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Affiliation(s)
- Yuedi Zhang
- Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Qiulin Cui
- Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Manman Xu
- Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Duo Liu
- Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shuzhong Yao
- Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Ming Chen, ; Shuzhong Yao,
| | - Ming Chen
- Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Ming Chen, ; Shuzhong Yao,
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17
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A Micro-Immunotherapy Sequential Medicine MIM-seq Displays Immunomodulatory Effects on Human Macrophages and Anti-Tumor Properties towards In Vitro 2D and 3D Models of Colon Carcinoma and in an In Vivo Subcutaneous Xenograft Colon Carcinoma Model. Int J Mol Sci 2022; 23:ijms23116059. [PMID: 35682738 PMCID: PMC9181410 DOI: 10.3390/ijms23116059] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 11/25/2022] Open
Abstract
In this study, the immunomodulatory effects of a sequential micro-immunotherapy medicine, referred as MIM-seq, were appraised in human primary M1 and M2 macrophages, in which the secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-12, IL-23, and tumor necrosis factor (TNF)-alpha, was inhibited. In addition, the potential anti-proliferative effects of MIM-seq on tumor cells was assessed in three models of colorectal cancer (CRC): an in vitro two-dimensions (2D) model of HCT-116 cells, an in vitro tri-dimensional (3D) model of spheroids, and an in vivo model of subcutaneous xenografted mice. In these models, MIM-seq displayed anti-proliferative effects when compared with the vehicle. In vivo, the tumor growth was slightly reduced in MIM-seq-treated animals. Moreover, MIM-seq could slightly reduce the growth of our spheroid models, especially under serum-deprivation. When MIM-seq was combined with two well-known anti-cancerogenic agents, either resveratrol or etoposide, MIM-seq could even further reduce the spheroid’s volume, pointing up the need to further assess whether MIM-seq could be beneficial for CRC patients as an adjuvant therapy. Altogether, these data suggest that MIM-seq could have anti-tumor properties against CRC and an immunomodulatory effect towards the mediators of inflammation, whose systemic dysregulation is considered to be a poor prognosis for patients.
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18
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Horowitz NB, Mohammad I, Moreno-Nieves UY, Koliesnik I, Tran Q, Sunwoo JB. Humanized Mouse Models for the Advancement of Innate Lymphoid Cell-Based Cancer Immunotherapies. Front Immunol 2021; 12:648580. [PMID: 33968039 PMCID: PMC8100438 DOI: 10.3389/fimmu.2021.648580] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
Innate lymphoid cells (ILCs) are a branch of the immune system that consists of diverse circulating and tissue-resident cells, which carry out functions including homeostasis and antitumor immunity. The development and behavior of human natural killer (NK) cells and other ILCs in the context of cancer is still incompletely understood. Since NK cells and Group 1 and 2 ILCs are known to be important for mediating antitumor immune responses, a clearer understanding of these processes is critical for improving cancer treatments and understanding tumor immunology as a whole. Unfortunately, there are some major differences in ILC differentiation and effector function pathways between humans and mice. To this end, mice bearing patient-derived xenografts or human cell line-derived tumors alongside human genes or human immune cells represent an excellent tool for studying these pathways in vivo. Recent advancements in humanized mice enable unparalleled insights into complex tumor-ILC interactions. In this review, we discuss ILC behavior in the context of cancer, the humanized mouse models that are most commonly employed in cancer research and their optimization for studying ILCs, current approaches to manipulating human ILCs for antitumor activity, and the relative utility of various mouse models for the development and assessment of these ILC-related immunotherapies.
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Affiliation(s)
- Nina B Horowitz
- Department of Otolaryngology-Head and Neck Surgery, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States.,Department of Bioengineering, Stanford University School of Medicine and School of Engineering, Stanford, CA, United States
| | - Imran Mohammad
- Department of Otolaryngology-Head and Neck Surgery, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Uriel Y Moreno-Nieves
- Department of Otolaryngology-Head and Neck Surgery, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Ievgen Koliesnik
- Department of Otolaryngology-Head and Neck Surgery, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Quan Tran
- Department of Otolaryngology-Head and Neck Surgery, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - John B Sunwoo
- Department of Otolaryngology-Head and Neck Surgery, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
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19
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Thomas R, Al-Khadairi G, Decock J. Immune Checkpoint Inhibitors in Triple Negative Breast Cancer Treatment: Promising Future Prospects. Front Oncol 2021; 10:600573. [PMID: 33718107 PMCID: PMC7947906 DOI: 10.3389/fonc.2020.600573] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 12/30/2020] [Indexed: 12/15/2022] Open
Abstract
Immunotherapy has emerged as the fifth pillar of cancer treatment alongside surgery, radiotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors are the current superheroes of immunotherapy, unleashing a patient's own immune cells to kill tumors and revolutionizing cancer treatment in a variety of cancers. Although breast cancer was historically believed to be immunologically silent, treatment with immune checkpoint inhibitors has been shown to induce modest responses in metastatic breast cancer. Given the inherent heterogeneity of breast tumors, this raised the question whether certain breast tumors might benefit more from immune-based interventions and which cancer cell-intrinsic and/or microenvironmental factors define the likelihood of inducing a potent and durable anti-tumor immune response. In this review, we will focus on triple negative breast cancer as immunogenic breast cancer subtype, and specifically discuss the relevance of tumor mutational burden, the plethora and diversity of tumor infiltrating immune cells in addition to the immunoscore, the presence of immune checkpoint expression, and the microbiome in defining immune checkpoint blockade response. We will highlight the current immune checkpoint inhibitor treatment options, either as monotherapy or in combination with standard-of-care treatment modalities such as chemotherapy and targeted therapy. In addition, we will look into the potential of immunotherapy-based combination strategies using immune checkpoint inhibitors to enhance both innate and adaptive immune responses, or to establish a more immune favorable environment for cancer vaccines. Finally, the review will address the need for unambiguous predictive biomarkers as one of the main challenges of immune checkpoint blockade. To conclude, the potential of immune checkpoint blockade for triple negative breast cancer treatment could be enhanced by exploration of aforementioned factors and treatment strategies thereby providing promising future prospects.
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Affiliation(s)
- Remy Thomas
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Ghaneya Al-Khadairi
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Julie Decock
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
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20
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Jindal A, Sarkar S, Alam A. Nanomaterials-Mediated Immunomodulation for Cancer Therapeutics. Front Chem 2021; 9:629635. [PMID: 33708759 PMCID: PMC7940769 DOI: 10.3389/fchem.2021.629635] [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: 11/15/2020] [Accepted: 01/18/2021] [Indexed: 12/16/2022] Open
Abstract
Immunotherapy holds great promise in overcoming the limitations of conventional regimens for cancer therapeutics. There is growing interest among researchers and clinicians to develop novel immune-strategies for cancer diagnosis and treatment with better specificity and lesser adversity. Immunomodulation-based cancer therapies are rapidly emerging as an alternative approach that employs the host's own defense mechanisms to recognize and selectively eliminate cancerous cells. Recent advances in nanotechnology have pioneered a revolution in the field of cancer therapy. Several nanomaterials (NMs) have been utilized to surmount the challenges of conventional anti-cancer treatments like cytotoxic chemotherapy, radiation, and surgery. NMs offer a plethora of exceptional features such as a large surface area to volume ratio, effective loading, and controlled release of active drugs, tunable dimensions, and high stability. Moreover, they also possess the inherent property of interacting with living cells and altering the immune responses. However, the interaction between NMs and the immune system can give rise to unanticipated adverse reactions such as inflammation, necrosis, and hypersensitivity. Therefore, to ensure a successful and safe clinical application of immunomodulatory nanomaterials, it is imperative to acquire in-depth knowledge and a clear understanding of the complex nature of the interactions between NMs and the immune system. This review is aimed at providing an overview of the recent developments, achievements, and challenges in the application of immunomodulatory nanomaterials (iNMs) for cancer therapeutics with a focus on elucidating the mechanisms involved in the interplay between NMs and the host's immune system.
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Affiliation(s)
- Ajita Jindal
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Sounik Sarkar
- Flowcytometry Facility, Modern Biology Department, University of Calcutta, Kolkata, India
| | - Aftab Alam
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
- Clare Hall, University of Cambridge, Cambridge, United Kingdom
- Charles River Laboratories, Cambridge Biomedical Campus, Cambridge, United Kingdom
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21
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Quevedo-Tinoco L, Rodríguez-García G, del Río RE, Talero E, Motilva V, Cerda-García-Rojas CM, Joseph-Nathan P, Gómez-Hurtado MA. Strategy for the vibrational circular dichroism study of a glycosylflavonoid evaluated as its peracetate. The case of bioactive 7-O-β-D-glucopyranosylchrysin. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2020.129147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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22
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Li J, Zhang Y, Cui Y, Jin H, Lin Z, Piao Y, Jin J. CD44 enhances adriamycin resistance in chronic myelogenous leukaemia cells K562. Int J Lab Hematol 2021; 43:983-989. [PMID: 33411349 DOI: 10.1111/ijlh.13455] [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: 08/07/2020] [Revised: 11/23/2020] [Accepted: 12/16/2020] [Indexed: 11/27/2022]
Abstract
INTRODUCTION To investigate CD44 effects on the adriamycin-resistant in chronic myelogenous leukaemia cells K562, we explored the role of CD44 in the K562 cells migration and apoptosis. METHODS GeneChip® screening is used for elucidating various chemoresistance-related gene expression in the adriamycin-resistant leukaemia cells K562/ADR. We constructed K562/CD44 cells by transfection of an EGFP-SV40-CD44 plasmid, and adriamycin-resistant ability was confirmed by detecting migration and apoptosis-related proteins and mRNA expression using Western blotting and Real-time PCR respectively. RESULTS K562/CD44 cells were generated by the transfection of an EGFP-SV40-CD44 plasmid with high CD44 expression. mRNA expression levels of CD44 and P-glycoprotein (P-gp), along with the proliferation rate, were increased, while the apoptosis rate of K562/CD44 cells was decreased. Migration-associated proteins such as MMP-2 and MMP-9 were upregulated, whereas apoptosis-related protein Bax was downregulated and Bcl-2 protein was not significantly altered in the K562/CD44 cells. CONCLUSIONS CD44 might be involved in adriamycin resistance via regulation of P-gp, MMP-2, MMP-9, and Bcl-2/Bax.
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Affiliation(s)
- Juan Li
- Department of Internal Medicine, The Affiliated Hospital of Yanbian University, Yanji, China.,Department of Rheumatology and Immunology, The First Affiliated Hospital of Luohe Medical College (Luohe Central Hospital), Luohe, China
| | - Yanfang Zhang
- Department of Internal Medicine, The Affiliated Hospital of Yanbian University, Yanji, China.,Department of Rheumatology and Immunology, Zhejiang Hospital, Hangzhou, China
| | - Yubo Cui
- Department of Internal Medicine, The Affiliated Hospital of Yanbian University, Yanji, China.,Department of Respiratory, Yanbian No. 2 People's Hospital, Yanji, China
| | - Honghua Jin
- Department of Internal Medicine, The Affiliated Hospital of Yanbian University, Yanji, China
| | - Zhenhua Lin
- Department of Internal Medicine, The Affiliated Hospital of Yanbian University, Yanji, China.,Key Laboratory of the Science and Technology Department (Jilin Province), Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Yingshi Piao
- Key Laboratory of the Science and Technology Department (Jilin Province), Cancer Research Center, Yanbian University Medical College, Yanji, China
| | - Jingchun Jin
- Department of Internal Medicine, The Affiliated Hospital of Yanbian University, Yanji, China.,Key Laboratory of the Science and Technology Department (Jilin Province), Cancer Research Center, Yanbian University Medical College, Yanji, China
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23
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García-Martínez E, Pérez-Fidalgo JA. Immunotherapies in ovarian cancer. EJC Suppl 2020; 15:87-95. [PMID: 33240447 PMCID: PMC7573463 DOI: 10.1016/j.ejcsup.2020.02.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 02/18/2020] [Accepted: 02/29/2020] [Indexed: 01/21/2023] Open
Abstract
Ovarian cancer is the leading cause of death for gynaecological cancer, and new therapies are urgently awaited. Although the presence of tumour-infiltrating lymphocytes has been confirmed to be associated to a better prognosis, immunotherapy is not yet incorporated to the armamentarium in ovarian cancer. This review briefly summarises the strategies that have been tested or are under study for the three different groups of tumours: immune desert, inflamed and immune-excluded ovarian tumours. Finally, a better knowledge of the biology and immune microenvironment is needed for successfully developing new immunotherapy strategies.
Immune ovarian cancer subtypes could improve the selection patients for immunotherapy. Very frequently ovarian cancer needs to be converted in an inflamed tumour. Checkpoints inhibitor combinations are well designed and very promising in ovarian cancer.
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Affiliation(s)
- Elena García-Martínez
- Department of Medical Oncology, Hospital Universitario Morales Meseguer, Instituto Murciano de Investigación Biosanitaria (IMIB), Grupo Español de Investigación en Cáncer de Ovario (GEICO), Murcia, Spain
| | - J Alejandro Pérez-Fidalgo
- Department of Medical Oncology, Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria INCLIVA, Grupo Español de Investigación en Cáncer de Ovario (GEICO), Valencia, Spain
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24
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The immuno-oncological challenge of COVID-19. ACTA ACUST UNITED AC 2020; 1:946-964. [DOI: 10.1038/s43018-020-00122-3] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023]
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25
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Johdi NA, Sukor NF. Colorectal Cancer Immunotherapy: Options and Strategies. Front Immunol 2020; 11:1624. [PMID: 33042104 PMCID: PMC7530194 DOI: 10.3389/fimmu.2020.01624] [Citation(s) in RCA: 287] [Impact Index Per Article: 57.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/17/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is the third most common cancer in the world with increasing incidence and mortality rates globally. Standard treatments for colorectal cancer have always been surgery, chemotherapy and radiotherapy which may be used in combination to treat patients. However, these treatments have many side effects due to their non-specificity and cytotoxicity toward any cells including normal cells that are growing and dividing. Furthermore, many patients succumb to relapse even after a series of treatments. Thus, it is crucial to have more alternative and effective treatments to treat CRC patients. Immunotherapy is one of the new alternatives in cancer treatment. The strategy is to utilize patients' own immune systems in combating the cancer cells. Cancer immunotherapy overcomes the issue of specificity which is the major problem in chemotherapy and radiotherapy. The normal cells with no cancer antigens are not affected. The outcomes of some cancer immunotherapy have been astonishing in some cases, but some which rely on the status of patients' own immune systems are not. Those patients who responded well to cancer immunotherapy have a better prognostic and better quality of life.
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Affiliation(s)
- Nor Adzimah Johdi
- UKM Medical Molecular Biology Institute (UMBI), National University of Malaysia, Bangi, Malaysia
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26
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Pilones KA, Charpentier M, Garcia-Martinez E, Demaria S. IL15 synergizes with radiotherapy to reprogram the tumor immune contexture through a dendritic cell connection. Oncoimmunology 2020; 9:1790716. [PMID: 32934886 PMCID: PMC7466855 DOI: 10.1080/2162402x.2020.1790716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
IL15 is a key cytokine for the activation and survival of anti-tumor effectors CD8+ T and NK cells. Recently published preclinical studies demonstrate that the therapeutic activity of IL15 requires conventional dendritic cells type 1 (cDC1). Radiotherapy cooperates with IL15 by enhancing cDC1 tumor infiltration via interferon type 1 activation.
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Affiliation(s)
- Karsten A Pilones
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Maud Charpentier
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Elena Garcia-Martinez
- Hematology and Oncology Department, Hospital Universitario Morales Meseguer, Murcia, Spain
| | - Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.,Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
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27
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Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy? Cells 2020; 9:cells9040829. [PMID: 32235616 PMCID: PMC7226769 DOI: 10.3390/cells9040829] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 03/27/2020] [Accepted: 03/28/2020] [Indexed: 12/22/2022] Open
Abstract
Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of Vγ9Vδ2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as γδ Chimeric Antigen Receptor (CAR) -T cells and γδ T-cell engagers are currently under preclinical evaluation. Since the impact of factors, such as the relatively low abundance of γδ T cells within tumor tissue is still under investigation, it remains to be shown whether these effector T cells can provide significant efficacy against solid tumors. Here, we highlight key learnings from the natural role of Vγ9Vδ2 T cells in the elimination of host cells bearing intracellular bacterial agents and we translate these into the setting of tumor therapy. We discuss the availability and relevance of preclinical models as well as currently available tools and knowledge from a drug development perspective. Finally, we compare advantages and disadvantages of existing therapeutic concepts and propose a role for Vγ9Vδ2 T cells in immune-oncology next to Cluster of Differentiation (CD) 3 activating therapies.
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28
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Affiliation(s)
- Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States; Sandra and Edward Meyer Cancer Center, New York, NY, United States; Caryl and Israel Englander Institute for Precision Medicine; Department of Dermatology, Yale University School of Medicine, New Haven, CT, United States; Université de Paris, Paris, France.
| | - Nils-Petter Rudqvist
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States.
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29
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Dobrovolskaia MA. Nucleic Acid Nanoparticles at a Crossroads of Vaccines and Immunotherapies. Molecules 2019; 24:molecules24244620. [PMID: 31861154 PMCID: PMC6943637 DOI: 10.3390/molecules24244620] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/13/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
Vaccines and immunotherapies involve a variety of technologies and act through different mechanisms to achieve a common goal, which is to optimize the immune response against an antigen. The antigen could be a molecule expressed on a pathogen (e.g., a disease-causing bacterium, a virus or another microorganism), abnormal or damaged host cells (e.g., cancer cells), environmental agent (e.g., nicotine from a tobacco smoke), or an allergen (e.g., pollen or food protein). Immunogenic vaccines and therapies optimize the immune response to improve the eradication of the pathogen or damaged cells. In contrast, tolerogenic vaccines and therapies retrain or blunt the immune response to antigens, which are recognized by the immune system as harmful to the host. To optimize the immune response to either improve the immunogenicity or induce tolerance, researchers employ different routes of administration, antigen-delivery systems, and adjuvants. Nanocarriers and adjuvants are of particular interest to the fields of vaccines and immunotherapy as they allow for targeted delivery of the antigens and direct the immune response against these antigens in desirable direction (i.e., to either enhance immunogenicity or induce tolerance). Recently, nanoparticles gained particular attention as antigen carriers and adjuvants. This review focuses on a particular subclass of nanoparticles, which are made of nucleic acids, so-called nucleic acid nanoparticles or NANPs. Immunological properties of these novel materials and considerations for their clinical translation are discussed.
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Affiliation(s)
- Marina A Dobrovolskaia
- Nanotechnology Characterization Lab, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702, USA
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30
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Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov 2019; 18:197-218. [PMID: 30610226 DOI: 10.1038/s41573-018-0007-y] [Citation(s) in RCA: 2176] [Impact Index Per Article: 362.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In this Review, we focus on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and we describe approaches to treat such tumours with combination immunotherapies, including checkpoint inhibitors. In the upcoming era of combination immunotherapy, it is becoming critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity. The impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.
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31
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Interleukin 21 Receptor/Ligand Interaction Is Linked to Disease Progression in Pancreatic Cancer. Cells 2019; 8:cells8091104. [PMID: 31540511 PMCID: PMC6770770 DOI: 10.3390/cells8091104] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/04/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) displays a marked fibro-inflammatory microenvironment in which infiltrated immune cells fail to eliminate the tumor cells and often—rather paradoxically—promote tumor progression. Of special interest are tumor-promoting T cells that assume a Th17-like phenotype because their presence in PDAC tissue is associated with a poor prognosis. In that context, the role of IL-21, a major cytokine released by Th17-like cells, was assessed. In all tissue samples (n = 264) IL-21+ immune cells were detected by immunohistochemistry and high density of those cells was associated with poor prognosis. In the majority of patients (221/264), tumor cells expressed the receptor for IL-21 (IL-21R) and also a downstream target of IL-21, Blimp-1 (199/264). Blimp-1 expression closely correlated with IL-21R expression and multivariate analysis revealed that expression of both IL-21R and Blimp-1 was associated with shorter survival time of the patients. In vitro data using pancreatic tumor cells lines provided a possible explanation: IL-21 activated ERK and STAT3 pathways and upregulated Blimp-1. Moreover, IL-21 increased invasion of tumor cell lines in a Blimp-1-dependent manner. As an in vivo correlate, an avian xenograft model was used. Here again Blimp-1 expression was significantly upregulated in IL-21 stimulated tumor cells. In summary, our data showed an association of IL-21+ immune cell infiltration and IL-21 receptor expression in PDAC with poor survival, most likely due to an IL-21-mediated promotion of tumor cell invasion and enhanced colony formation, supporting the notion of the tumor-promoting abilities of the tumor microenvironment.
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32
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Cheng L, Meiser B. The relationship between psychosocial factors and biomarkers in cancer patients: A systematic review of the literature. Eur J Oncol Nurs 2019; 41:88-96. [DOI: 10.1016/j.ejon.2019.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/05/2019] [Accepted: 06/09/2019] [Indexed: 02/06/2023]
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33
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Role of cell surface proteoglycans in cancer immunotherapy. Semin Cancer Biol 2019; 62:48-67. [PMID: 31336150 DOI: 10.1016/j.semcancer.2019.07.012] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/05/2019] [Accepted: 07/17/2019] [Indexed: 12/23/2022]
Abstract
Over the past few decades, understanding how tumor cells evade the immune system and their communication with their tumor microenvironment, has been the subject of intense investigation, with the aim of developing new cancer immunotherapies. The current therapies against cancer such as monoclonal antibodies against checkpoint inhibitors, adoptive T-cell transfer, cytokines, vaccines, and oncolytic viruses have managed to improve the clinical outcome of the patients. However, in some tumor entities, the response is limited and could benefit from the identification of novel therapeutic targets. It is known that tumor-extracellular matrix interplay and matrix remodeling are necessary for anti-tumor and pro-tumoral immune responses. Proteoglycans are dominant components of the extracellular matrix and are a highly heterogeneous group of proteins characterized by the covalent attachment of a specific linear carbohydrate chain of the glycosaminoglycan type. At cell surfaces, these molecules modulate the expression and activity of cytokines, chemokines, growth factors, adhesion molecules, and function as signaling co-receptors. By these mechanisms, proteoglycans influence the behavior of cancer cells and their microenvironment during the progression of solid tumors and hematopoietic malignancies. In this review, we discuss why cell surface proteoglycans are attractive pharmacological targets in cancer, and we present current and recent developments in cancer immunology and immunotherapy utilizing proteoglycan-targeted strategies.
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34
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Expression of costimulatory and inhibitory receptors in FoxP3 + regulatory T cells within the tumor microenvironment: Implications for combination immunotherapy approaches. Adv Cancer Res 2019; 144:193-261. [PMID: 31349899 DOI: 10.1016/bs.acr.2019.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The unprecedented success of immune checkpoint inhibitors has given rise to a rapidly growing number of immuno-oncology agents undergoing preclinical and clinical development and an exponential increase in possible combinations. Defining a clear rationale for combinations by identifying synergies between immunomodulatory pathways has therefore become a high priority. Immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment (TME) represent a major roadblock to endogenous and therapeutic tumor immunity. However, Tregs are also essential for the maintenance of immunological self-tolerance, and share many molecular pathways with conventional T cells including cytotoxic T cells, the primary mediators of tumor immunity. Hence the inability to specifically target and neutralize Tregs within the TME of cancer patients without globally compromising self-tolerance poses a significant challenge. Here we review recent advances in the characterization of tumor-infiltrating Tregs with a focus on costimulatory and inhibitory receptors. We discuss receptor expression patterns, their functional role in Treg biology and mechanistic insights gained from targeting these receptors in preclinical models to evaluate their potential as clinical targets. We further outline a framework of parameters that could be used to refine the assessment of Tregs in cancer patients and increase their value as predictive biomarkers. Finally, we propose modalities to integrate our increasing knowledge on Treg phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Such combinations have great potential for synergy, as they could concomitantly enhance cytotoxic T cells and inhibit Tregs within the TME, thereby increasing the efficacy of current cancer immunotherapies.
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35
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Osipov A, Murphy A, Zheng L. From immune checkpoints to vaccines: The past, present and future of cancer immunotherapy. Adv Cancer Res 2019; 143:63-144. [PMID: 31202363 DOI: 10.1016/bs.acr.2019.03.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cancer is a worldwide medical problem with significant repercussions on individual patients and societies as a whole. In order to alter the outcomes of this deadly disease the treatment of cancer over the centuries has undergone a unique evolution. However, utilizing the best treatment modalities and achieving cures or long-term durable responses have been inconsistent and limited, that is until recently. Contemporary research has highlighted a fundamental gap in our understanding of how we approach treating cancer, by revealing the intricate relationship between the immune system and tumors. In this atmosphere, the growth of immunotherapy has not only forever changed our understanding of cancer biology, but the manner by which we treat patients. It's paradigm shifting success has led to the approval of over 10 different immunotherapeutic agents, including checkpoint inhibitors, vaccine-based therapies, oncolytic viruses and T cell directed therapies for nearly 20 different indications across countless tumor types. Despite the breakthroughs that have occurred in the field of immunotherapy, it has not been the panacea for all cancers. With a deeper understanding of the immune system we have been able to peer into tumor immune escape and therapy resistance. Simultaneously this understanding has paved the way for the investigation and development of novel immune system altering agents and combinatorial therapies. In this chapter we review the immune system and its intricate relationship with cancer, the evolution of immunotherapy, its current landscape, and future directions in the context of resistance mechanisms and the challenges faced by immunotherapy against cancer.
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Affiliation(s)
- Arsen Osipov
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Adrian Murphy
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Lei Zheng
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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36
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Wang K, Li HL, Xiong YF, Shi Y, Li ZY, Li J, Zhang X, Li HY. Development and validation of nomograms integrating immune-related genomic signatures with clinicopathologic features to improve prognosis and predictive value of triple-negative breast cancer: A gene expression-based retrospective study. Cancer Med 2019; 8:686-700. [PMID: 30677255 PMCID: PMC6382728 DOI: 10.1002/cam4.1880] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/06/2018] [Accepted: 10/27/2018] [Indexed: 02/05/2023] Open
Abstract
Purpose Accumulating evidence indicated that triple‐negative breast cancer (TNBC) can stimulate stronger immune responses than other subtypes of breast cancer. We hypothesized that integrating immune‐related genomic signatures with clinicopathologic factors may yield a predictive accuracy exceeding that of the currently available system. Methods Ten signatures that reflect specific immunogenic or immune microenvironmental features of TNBC were identified and re‐analyzed using bioinformatic methods. Then, clinically annotated TNBC (n = 711) with the corresponding expression profiles, which predicted a patient's probability of disease‐free survival (DFS) and overall survival (OS), was pooled to evaluate their prognostic values and establish a clinicopathologic‐genomic nomogram. Three and two immune features were, respectively, selected out of 10 immune features to construct nomogram for DFS and OS prediction based on multivariate backward stepwise Cox regression analyses. Results By integrating the above immune expression signatures with prognostic clinicopathologic features, clinicopathologic‐genomic nomograms were cautiously constructed, which showed reasonable prediction accuracies (DFS: HR, 1.79; 95% CI, 1.46‐2.18, P < 0.001; AUC, 0.71; OS: HR, 1.96; 95% CI, 1.54‐2.49; P < 0.001; AUC, 0.73). The nomogram showed low‐risk subgroup had higher immune checkpoint molecules (PD‐L1, PD‐1, CTLA‐4, LAG‐3) expression and benefited from radiotherapy (HR, 0.2, 95% CI, 0.05‐0.89; P = 0.034) rather than chemotherapy (HR, 1.26, 95% CI, 0.66‐2.43; P = 0.485). Conclusions These findings offer evidence that immune‐related genomic data provide independent and complementary prognostic information for TNBC, and the nomogram might be a practical predictive tool to identify TNBC patients who would benefit from chemotherapy, radiotherapy, and upcoming popularity of immunotherapy.
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Affiliation(s)
- Kang Wang
- Department of the Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Hai-Lin Li
- Department of the Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Yong-Fu Xiong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Yang Shi
- Division of Biostatistics and Data Science, Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, Georgia.,West China School of Public Health, Sichuan University, Chengdu, China
| | - Zhu-Yue Li
- Institute of Hospital Management, West China Hospital, Sichuan University, Chengdu, China.,West China Hospital/West China School of Nursing, Sichuan University, Chengdu, China
| | - Jie Li
- Department of the Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Xiang Zhang
- Department of the Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Hong-Yuan Li
- Department of the Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
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Affiliation(s)
- Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States; Sandra and Edward Meyer Cancer Center, New York, NY, United States; Department of Dermatology, Yale University School of Medicine, New Haven, CT, United States; Université Paris Descartes/Paris V, Paris, France.
| | - Nils-Petter Rudqvist
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States.
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38
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Vanpouille-Box C, Demaria S, Formenti SC, Galluzzi L. Cytosolic DNA Sensing in Organismal Tumor Control. Cancer Cell 2018; 34:361-378. [PMID: 30216189 DOI: 10.1016/j.ccell.2018.05.013] [Citation(s) in RCA: 191] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 04/11/2018] [Accepted: 05/30/2018] [Indexed: 02/07/2023]
Abstract
Besides constituting a first layer of defense against microbial challenges, the detection of cytosolic DNA is fundamental for mammalian organisms to control malignant transformation and tumor progression. The accumulation of DNA in the cytoplasm can initiate the proliferative inactivation (via cellular senescence) or elimination (via regulated cell death) of neoplastic cell precursors. Moreover, cytosolic DNA sensing is intimately connected to the secretion of cytokines that support innate and adaptive antitumor immunity. Here, we discuss the molecular mechanisms whereby cytosolic DNA enables cell-intrinsic and -extrinsic oncosuppression, and their relevance for the development of novel therapeutic approaches that reinstate anticancer immunosurveillance.
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Affiliation(s)
- Claire Vanpouille-Box
- Department of Radiation Oncology, Weill Cornell Medical College, Stich Radiation Oncology, 525 East 68th Street, Box #169, New York, NY 10065, USA
| | - Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medical College, Stich Radiation Oncology, 525 East 68th Street, Box #169, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Silvia C Formenti
- Department of Radiation Oncology, Weill Cornell Medical College, Stich Radiation Oncology, 525 East 68th Street, Box #169, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, Stich Radiation Oncology, 525 East 68th Street, Box #169, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Université Paris Descartes/Paris V, Paris, France.
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