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Kina E, Larouche JD, Thibault P, Perreault C. The cryptic immunopeptidome in health and disease. Trends Genet 2025; 41:162-169. [PMID: 39389870 DOI: 10.1016/j.tig.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 08/01/2024] [Accepted: 09/17/2024] [Indexed: 10/12/2024]
Abstract
Peptides presented by MHC proteins regulate all aspects of T cell biology. These MHC-associated peptides (MAPs) form what is known as the immunopeptidome and their comprehensive analysis has catalyzed the burgeoning field of immunopeptidomics. Advances in mass spectrometry (MS) and next-generation sequencing have facilitated significant breakthroughs in this area, some of which are highlighted in this article on the cryptic immunopeptidome. Here, 'cryptic' refers to peptides and proteins encoded by noncanonical open reading frames (ORFs). Cryptic MAPs derive mainly from short unstable proteins found in normal, infected, and neoplastic cells. Cryptic MAPs show minimal overlap with cryptic proteins found in whole-cell extracts. In many cancer types, most cancer-specific MAPs are cryptic.
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Affiliation(s)
- Eralda Kina
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada
| | - Jean-David Larouche
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada
| | - Pierre Thibault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada
| | - Claude Perreault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.
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2
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Aggeletopoulou I, Pantzios S, Triantos C. Personalized Immunity: Neoantigen-Based Vaccines Revolutionizing Hepatocellular Carcinoma Treatment. Cancers (Basel) 2025; 17:376. [PMID: 39941745 PMCID: PMC11815775 DOI: 10.3390/cancers17030376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/16/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, presents significant therapeutic challenges due to its molecular complexity, late-stage diagnosis, and inherent resistance to conventional treatments. The intermediate to low mutational burden in HCC and its ability to evade the immune system through multiple mechanisms complicate the development of effective therapies. Recent advancements in immunotherapy, particularly neoantigen-based vaccines, offer a promising, personalized approach to HCC treatment. Neoantigens are tumor-specific peptides derived from somatic mutations in tumor cells. Unlike normal cellular antigens, neoantigens are foreign to the immune system, making them highly specific targets for immunotherapy. Neoantigens arise from genetic alterations such as point mutations, insertions, deletions, and gene fusions, which are expressed as neoepitopes that are not present in healthy tissues, thus evading the immune tolerance mechanisms that typically protect normal cells. Preclinical and early-phase clinical studies of neoantigen-based vaccines have shown promising results, demonstrating the ability of these vaccines to elicit robust T cell responses against HCC. The aim of the current review is to provide an in-depth exploration of the therapeutic potential of neoantigen-based vaccines in HCC, focusing on neoantigen identification, vaccine platforms, and their integration with immune checkpoint inhibitors to enhance immunogenicity. It also evaluates preclinical and clinical data on efficacy and safety while addressing challenges in clinical translation. By taking advantage of the unique antigenic profile of each patient's tumor, neoantigen-based vaccines represent a promising approach in the treatment of HCC, offering the potential for improved patient outcomes, long-term remission, and a shift towards personalized, precision medicine in liver cancer therapy.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece;
| | - Spyridon Pantzios
- Hepatogastroenterology Unit, Academic Department of Internal Medicine, General Oncology Hospital of Kifissia “Agioi Anargyroi”, National and Kapodistrian University of Athens, 14564 Athens, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece;
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3
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Blay V, Pandiella A. Strategies to boost antibody selectivity in oncology. Trends Pharmacol Sci 2024; 45:1135-1149. [PMID: 39609227 DOI: 10.1016/j.tips.2024.10.005] [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: 07/22/2024] [Revised: 09/03/2024] [Accepted: 10/18/2024] [Indexed: 11/30/2024]
Abstract
Antibodies in oncology are being equipped with toxic cargoes and effector functions that can kill cells at very low concentrations. A key challenge is that most targets on cancer cells are also present on at least some healthy cells. Shared targets can result in off-tumor binding and compromise the safety and potential of therapeutic candidates. In this review, we survey strategies that can help direct biologics to cancer sites more selectively. These strategies are becoming increasingly feasible thanks to advances in molecular design and engineering. The objective is to create therapeutics that exploit changes in cancer and leverage the human body infrastructure, enabling therapeutics that discriminate not just self from non-self but diseased from healthy tissue.
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Affiliation(s)
- Vincent Blay
- University of California Santa Cruz, Department of Microbiology and Environmental Toxicology, Santa Cruz, CA 95064, USA.
| | - Atanasio Pandiella
- Centro de Investigación del Cáncer, CIBERONC and IBSAL, 37007 Salamanca, Spain
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4
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Karimi-Sani I, Molavi Z, Naderi S, Mirmajidi SH, Zare I, Naeimzadeh Y, Mansouri A, Tajbakhsh A, Savardashtaki A, Sahebkar A. Personalized mRNA vaccines in glioblastoma therapy: from rational design to clinical trials. J Nanobiotechnology 2024; 22:601. [PMID: 39367418 PMCID: PMC11453023 DOI: 10.1186/s12951-024-02882-x] [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: 06/03/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024] Open
Abstract
Glioblastomas (GBMs) are the most common and aggressive malignant brain tumors, presenting significant challenges for treatment due to their invasive nature and localization in critical brain regions. Standard treatment includes surgical resection followed by radiation and adjuvant chemotherapy with temozolomide (TMZ). Recent advances in immunotherapy, including the use of mRNA vaccines, offer promising alternatives. This review focuses on the emerging use of mRNA vaccines for GBM treatment. We summarize recent advancements, evaluate current obstacles, and discuss notable successes in this field. Our analysis highlights that while mRNA vaccines have shown potential, their use in GBM treatment is still experimental. Ongoing research and clinical trials are essential to fully understand their therapeutic potential. Future developments in mRNA vaccine technology and insights into GBM-specific immune responses may lead to more targeted and effective treatments. Despite the promise, further research is crucial to validate and optimize the effectiveness of mRNA vaccines in combating GBM.
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Affiliation(s)
- Iman Karimi-Sani
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Molavi
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Naderi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyedeh-Habibeh Mirmajidi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Iman Zare
- Research and Development Department, Sina Medical Biochemistry Technologies Co. Ltd., Shiraz, 7178795844, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Atena Mansouri
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
- Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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5
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Yin Z(S, Wang Z. Strategies for engineering oncolytic viruses to enhance cancer immunotherapy. Front Pharmacol 2024; 15:1450203. [PMID: 39309012 PMCID: PMC11413971 DOI: 10.3389/fphar.2024.1450203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 07/30/2024] [Indexed: 09/25/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer and is characterized by rapid metastasis and high mortality, presenting a challenge for early-stage treatment modalities. The heterogeneity of NSCLC's tumor microenvironment (TME) significantly influences the efficacy of anti-PD-1 immune checkpoint inhibitors (ICIs) therapy, leading to varied patient responses. This review characterized different strains of oncolytic viruses in NSCLC and the different gene edits in pre-existing oncolytic viruses. This study also aimed to provide strategies to enhance anti-PD-1 therapy in NSCLC by engineering oncolytic viruses (OVs). This study offers insights into the genomic adaptations necessary for OVs targeting NSCLC, identify genetic determinants of anti-PD-1 response variability, and propose genomic edits to bolster therapy effectiveness. The primary goal of this study is to present a theoretically designed OV with a detailed genomic framework capable of enhancing the response to anti-PD-1 therapy, thereby advancing the field of cancer immunotherapy.
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Affiliation(s)
| | - Zhengfeng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Flender D, Vilenne F, Adams C, Boonen K, Valkenborg D, Baggerman G. Exploring the dynamic landscape of immunopeptidomics: Unravelling posttranslational modifications and navigating bioinformatics terrain. MASS SPECTROMETRY REVIEWS 2024. [PMID: 39152539 DOI: 10.1002/mas.21905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 08/19/2024]
Abstract
Immunopeptidomics is becoming an increasingly important field of study. The capability to identify immunopeptides with pivotal roles in the human immune system is essential to shift the current curative medicine towards personalized medicine. Throughout the years, the field has matured, giving insight into the current pitfalls. Nowadays, it is commonly accepted that generalizing shotgun proteomics workflows is malpractice because immunopeptidomics faces numerous challenges. While many of these difficulties have been addressed, the road towards the ideal workflow remains complicated. Although the presence of Posttranslational modifications (PTMs) in the immunopeptidome has been demonstrated, their identification remains highly challenging despite their significance for immunotherapies. The large number of unpredictable modifications in the immunopeptidome plays a pivotal role in the functionality and these challenges. This review provides a comprehensive overview of the current advancements in immunopeptidomics. We delve into the challenges associated with identifying PTMs within the immunopeptidome, aiming to address the current state of the field.
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Affiliation(s)
- Daniel Flender
- Centre for Proteomics, University of Antwerp, Antwerpen, Belgium
- Health Unit, VITO, Mol, Belgium
| | - Frédérique Vilenne
- Health Unit, VITO, Mol, Belgium
- Data Science Institute, University of Hasselt, Hasselt, Belgium
| | - Charlotte Adams
- Department of Computer Science, University of Antwerp, Antwerp, Belgium
| | - Kurt Boonen
- Centre for Proteomics, University of Antwerp, Antwerpen, Belgium
- ImmuneSpec, Niel, Belgium
| | - Dirk Valkenborg
- Data Science Institute, University of Hasselt, Hasselt, Belgium
| | - Geert Baggerman
- Department of Computer Science, University of Antwerp, Antwerp, Belgium
- ImmuneSpec, Niel, Belgium
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7
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Desai N, Chavda V, Singh TRR, Thorat ND, Vora LK. Cancer Nanovaccines: Nanomaterials and Clinical Perspectives. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2401631. [PMID: 38693099 DOI: 10.1002/smll.202401631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 03/30/2024] [Indexed: 05/03/2024]
Abstract
Cancer nanovaccines represent a promising frontier in cancer immunotherapy, utilizing nanotechnology to augment traditional vaccine efficacy. This review comprehensively examines the current state-of-the-art in cancer nanovaccine development, elucidating innovative strategies and technologies employed in their design. It explores both preclinical and clinical advancements, emphasizing key studies demonstrating their potential to elicit robust anti-tumor immune responses. The study encompasses various facets, including integrating biomaterial-based nanocarriers for antigen delivery, adjuvant selection, and the impact of nanoscale properties on vaccine performance. Detailed insights into the complex interplay between the tumor microenvironment and nanovaccine responses are provided, highlighting challenges and opportunities in optimizing therapeutic outcomes. Additionally, the study presents a thorough analysis of ongoing clinical trials, presenting a snapshot of the current clinical landscape. By curating the latest scientific findings and clinical developments, this study aims to serve as a comprehensive resource for researchers and clinicians engaged in advancing cancer immunotherapy. Integrating nanotechnology into vaccine design holds immense promise for revolutionizing cancer treatment paradigms, and this review provides a timely update on the evolving landscape of cancer nanovaccines.
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Affiliation(s)
- Nimeet Desai
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, 502285, India
| | - Vivek Chavda
- Department of Pharmaceutics and Pharmaceutical Technology, L M College of Pharmacy, Ahmedabad, 380009, India
| | | | - Nanasaheb D Thorat
- Limerick Digital Cancer Research Centre (LDCRC), University of Limerick, Castletroy, Limerick, V94T9PX, Ireland
- Department of Physics, Bernal Institute, Castletroy, Limerick, V94T9PX, Ireland
- Nuffield Department of Women's & Reproductive Health, Medical Science Division, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Lalitkumar K Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
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8
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Yao X, Matosevic S. Generation and evaluation of cancer binding capacity of HLA-A2-WT1 complex-targeting antibody. Immunol Lett 2024; 268:106881. [PMID: 38810886 DOI: 10.1016/j.imlet.2024.106881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 05/03/2024] [Accepted: 05/26/2024] [Indexed: 05/31/2024]
Abstract
Wilms' tumor (WT1), a transcription factor highly expressed in various leukemias and solid tumors, is a highly specific intracellular tumor antigen, requiring presentation through complexation with HLA-restricted peptides.. WT1-derived epitopes are able to assemble with MHC-I and thereby be recognized by T cell receptors (TCR). Identification of new targetable epitopes derived from WT1 on solid tumors is a challenge, but meaningful for the development of therapeutics that could in this way target intracellular oncogenic proteins. In this study, we developed and comprehensively describe methods to validate the formation of the complex of WT1126-134 and HLA-A2. Subsequently, we developed an antibody fragment able to recognize the extracellular complex on the surface of cancer cells. The single chain variable fragment (scFv) of an established TCR-mimic antibody, specifically recognizing the WT1-derived peptide presented by the HLA-A2 complex, was expressed, purified, and functionally validated using a T2 cell antigen presentation model. Furthermore, we evaluated the potential of the WT1-derived peptide as a targetable extracellular antigen in multiple solid tumor cell lines. Our study describes methodology for the evaluation of WT1-derived peptides as tumor-specific antigen on solid tumors, and may facilitate the selection of potential candidates for future immunotherapy targeting WT1 epitopes.
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MESH Headings
- Humans
- WT1 Proteins/immunology
- WT1 Proteins/metabolism
- HLA-A2 Antigen/immunology
- HLA-A2 Antigen/metabolism
- Cell Line, Tumor
- Neoplasms/immunology
- Neoplasms/metabolism
- Neoplasms/therapy
- Protein Binding
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Single-Chain Antibodies/immunology
- Single-Chain Antibodies/genetics
- Single-Chain Antibodies/metabolism
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/genetics
- Antigen Presentation/immunology
- Epitopes/immunology
- Epitopes, T-Lymphocyte/immunology
- Epitopes, T-Lymphocyte/metabolism
- Peptides/immunology
- Peptides/chemistry
- Peptides/metabolism
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Affiliation(s)
- Xue Yao
- Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN, USA
| | - Sandro Matosevic
- Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN, USA; Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
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9
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Becker JC, Stang A, Schrama D, Ugurel S. Merkel Cell Carcinoma: Integrating Epidemiology, Immunology, and Therapeutic Updates. Am J Clin Dermatol 2024; 25:541-557. [PMID: 38649621 PMCID: PMC11193695 DOI: 10.1007/s40257-024-00858-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2024] [Indexed: 04/25/2024]
Abstract
Merkel cell carcinoma (MCC) is a rare skin cancer characterized by neuroendocrine differentiation. Its carcinogenesis is based either on the integration of the Merkel cell polyomavirus or on ultraviolet (UV) mutagenesis, both of which lead to high immunogenicity either through the expression of viral proteins or neoantigens. Despite this immunogenicity resulting from viral or UV-associated carcinogenesis, it exhibits highly aggressive behavior. However, owing to the rarity of MCC and the lack of epidemiologic registries with detailed clinical data, there is some uncertainty regarding the spontaneous course of the disease. Historically, advanced MCC patients were treated with conventional cytotoxic chemotherapy yielding a median response duration of only 3 months. Starting in 2017, four programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors-avelumab, pembrolizumab, nivolumab (utilized in both neoadjuvant and adjuvant settings), and retifanlimab-have demonstrated efficacy in treating patients with disseminated MCC on the basis of prospective clinical trials. However, generating clinical evidence for rare cancers, such as MCC, is challenging owing to difficulties in conducting large-scale trials, resulting in small sample sizes and therefore lacking statistical power. Thus, to comprehensively understand the available clinical evidence on various immunotherapy approaches for MCC, we also delve into the epidemiology and immune biology of this cancer. Nevertheless, while randomized studies directly comparing immune checkpoint inhibitors and chemotherapy in MCC are lacking, immunotherapy shows response rates comparable to those previously reported with chemotherapy but with more enduring responses. Notably, adjuvant nivolumab has proven superiority to the standard-of-care therapy (observation) in the adjuvant setting.
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Affiliation(s)
- Jürgen C Becker
- Department of Translational Skin Cancer Research (TSCR), German Cancer Consortium (DKTK), partner site Essen, University Duisburg-Essen, Universitätsstrasse 1, 45141, Essen, Germany.
- Department of Dermatology, University Medicine Essen, Essen, Germany.
- German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Andreas Stang
- Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany
- Cancer Registry of North Rhine-Westphalia, Bochum, Germany
| | - David Schrama
- Department of Dermatology, University Hospital Würzburg, Würzburg, Germany
| | - Selma Ugurel
- Department of Dermatology, University Medicine Essen, Essen, Germany
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Subbarayan R, Srinivasan D, Balakrishnan R, Kumar A, Usmani SS, Srivastava N. DNA damage response and neoantigens: A favorable target for triple-negative breast cancer immunotherapy and vaccine development. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 389:104-152. [PMID: 39396845 DOI: 10.1016/bs.ircmb.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature and limited therapeutic options. The interplay between DNA damage response (DDR) mechanisms and the emergence of neoantigens represents a promising avenue for developing targeted immunotherapeutic strategies and vaccines for TNBC. The DDR is a complex network of cellular mechanisms designed to maintain genomic integrity. In TNBC, where genetic instability is a hallmark, dysregulation of DDR components plays a pivotal role in tumorigenesis and progression. This review explores the intricate relationship between DDR and neoantigens, shedding light on the potential vulnerabilities of TNBC cells. Neoantigens, arising from somatic mutations in cancer cells, represent unique antigens that can be recognized by the immune system. TNBC's propensity for genomic instability leads to an increased mutational burden, consequently yielding a rich repertoire of neoantigens. The convergence of DDR and neoantigens in TNBC offers a distinctive opportunity for immunotherapeutic targeting. Immunotherapy has revolutionized cancer treatment by harnessing the immune system to selectively target cancer cells. The unique immunogenicity conferred by DDR-related neoantigens in TNBC positions them as ideal targets for immunotherapeutic interventions. This review also explores various immunotherapeutic modalities, including immune checkpoint inhibitors (ICIs), adoptive cell therapies, and cancer vaccines, that leverage the DDR and neoantigen interplay to enhance anti-tumor immune responses. Moreover, the potential for developing vaccines targeting DDR-related neoantigens opens new frontiers in preventive and therapeutic strategies for TNBC. The rational design of vaccines tailored to the individual mutational landscape of TNBC holds promise for precision medicine approaches. In conclusion, the convergence of DDR and neoantigens in TNBC presents a compelling rationale for the development of innovative immunotherapies and vaccines. Understanding and targeting these interconnected processes may pave the way for personalized and effective interventions, offering new hope for patients grappling with the challenges posed by TNBCs.
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Affiliation(s)
- Rajasekaran Subbarayan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, FAHS, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Dhasarathdev Srinivasan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, FAHS, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Ranjith Balakrishnan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, FAHS, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Ajeet Kumar
- Department of Psychiatry, Washington university School of Medicine, St louis, MO, United States
| | - Salman Sadullah Usmani
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States.
| | - Nityanand Srivastava
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, United States.
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11
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Maso L, Rajak E, Bang I, Koide A, Hattori T, Neel BG, Koide S. Molecular basis for antibody recognition of multiple drug-peptide/MHC complexes. Proc Natl Acad Sci U S A 2024; 121:e2319029121. [PMID: 38781214 PMCID: PMC11145297 DOI: 10.1073/pnas.2319029121] [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: 10/30/2023] [Accepted: 02/14/2024] [Indexed: 05/25/2024] Open
Abstract
The HapImmuneTM platform exploits covalent inhibitors as haptens for creating major histocompatibility complex (MHC)-presented tumor-specific neoantigens by design, combining targeted therapies with immunotherapy for the treatment of drug-resistant cancers. A HapImmune antibody, R023, recognizes multiple sotorasib-conjugated KRAS(G12C) peptides presented by different human leukocyte antigens (HLAs). This high specificity to sotorasib, coupled with broad HLA-binding capability, enables such antibodies, when reformatted as T cell engagers, to potently and selectively kill sotorasib-resistant KRAS(G12C) cancer cells expressing different HLAs upon sotorasib treatment. The loosening of HLA restriction could increase the patient population that can benefit from this therapeutic approach. To understand the molecular basis for its unconventional binding capability, we used single-particle cryogenic electron microscopy to determine the structures of R023 bound to multiple sotorasib-peptide conjugates presented by different HLAs. R023 forms a pocket for sotorasib between the VH and VL domains, binds HLAs in an unconventional, angled way, with VL making most contacts with them, and makes few contacts with the peptide moieties. This binding mode enables the antibody to accommodate different hapten-peptide conjugates and to adjust its conformation to different HLAs presenting hapten-peptides. Deep mutational scanning validated the structures and revealed distinct levels of mutation tolerance by sotorasib- and HLA-binding residues. Together, our structural information and sequence landscape analysis reveal key features for achieving MHC-restricted recognition of multiple hapten-peptide antigens, which will inform the development of next-generation therapeutic antibodies.
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Affiliation(s)
- Lorenzo Maso
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY10016
| | - Epsa Rajak
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY10016
| | - Injin Bang
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY10016
| | - Akiko Koide
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY10016
- Department of Medicine, New York University School of Medicine, New York, NY10016
| | - Takamitsu Hattori
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY10016
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY10016
| | - Benjamin G. Neel
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY10016
- Department of Medicine, New York University School of Medicine, New York, NY10016
| | - Shohei Koide
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY10016
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY10016
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12
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Yang Z, Teng Y, Lin M, Peng Y, Du Y, Sun Q, Gao D, Yuan Q, Zhou Y, Yang Y, Li J, Zhou Y, Li X, Qi X. Reinforced Immunogenic Endoplasmic Reticulum Stress and Oxidative Stress via an Orchestrated Nanophotoinducer to Boost Cancer Photoimmunotherapy. ACS NANO 2024; 18:7267-7286. [PMID: 38382065 DOI: 10.1021/acsnano.3c13143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/23/2024]
Abstract
Cancer progression and treatment-associated cellular stress impairs therapeutic outcome by inducing resistance. Endoplasmic reticulum (ER) stress is responsible for core events. Aberrant activation of stress sensors and their downstream components to disrupt homeostasis have emerged as vital regulators of tumor progression as well as response to cancer therapy. Here, an orchestrated nanophotoinducer (ERsNP) results in specific tumor ER-homing, induces hyperthermia and mounting oxidative stress associated reactive oxygen species (ROS), and provokes intense and lethal ER stress upon near-infrared laser irradiation. The strengthened "dying" of ER stress and ROS subsequently induce apoptosis for both primary and abscopal B16F10 and GL261 tumors, and promote damage-associated molecular patterns to evoke stress-dependent immunogenic cell death effects and release "self-antigens". Thus, there is a cascade to activate maturation of dendritic cells, reprogram myeloid-derived suppressor cells to manipulate immunosuppression, and recruit cytotoxic T lymphocytes and effective antitumor response. The long-term protection against tumor recurrence is realized through cascaded combinatorial preoperative and postoperative photoimmunotherapy including the chemokine (C-C motif) receptor 2 antagonist, ERsNP upon laser irradiation, and an immune checkpoint inhibitor. The results highlight great promise of the orchestrated nanophotoinducer to exert potent immunogenic cell stress and death by reinforcing ER stress and oxidative stress to boost cancer photoimmunotherapy.
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Affiliation(s)
- Zhenzhen Yang
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
- Drug Clinical Trial Center, Institute of Medical Innovation and Research, Peking University Third Hospital, Peking University, Beijing 100191, P.R. China
| | - Yulu Teng
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Meng Lin
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Yiwei Peng
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Yitian Du
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Qi Sun
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Datong Gao
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Quan Yuan
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Yu Zhou
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Yiliang Yang
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Jiajia Li
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Yanxia Zhou
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Xinru Li
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
| | - Xianrong Qi
- Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China
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13
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Hassan MT, Tayara H, Chong KT. An integrative machine learning model for the identification of tumor T-cell antigens. Biosystems 2024; 237:105177. [PMID: 38458346 DOI: 10.1016/j.biosystems.2024.105177] [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: 10/03/2023] [Revised: 01/28/2024] [Accepted: 03/05/2024] [Indexed: 03/10/2024]
Abstract
The escalating global incidence of cancer poses significant health challenges, underscoring the need for innovative and more efficacious treatments. Cancer immunotherapy, a promising approach leveraging the body's immune system against cancer, emerges as a compelling solution. Consequently, the identification and characterization of tumor T-cell antigens (TTCAs) have become pivotal for exploration. In this manuscript, we introduce TTCA-IF, an integrative machine learning-based framework designed for TTCAs identification. TTCA-IF employs ten feature encoding types in conjunction with five conventional machine learning classifiers. To establish a robust foundation, these classifiers are trained, resulting in the creation of 150 baseline models. The outputs from these baseline models are then fed back into the five classifiers, generating their respective meta-models. Through an ensemble approach, the five meta-models are seamlessly integrated to yield the final predictive model, the TTCA-IF model. Our proposed model, TTCA-IF, surpasses both baseline models and existing predictors in performance. In a comparative analysis involving nine novel peptide sequences, TTCA-IF demonstrated exceptional accuracy by correctly identifying 8 out of 9 peptides as TTCAs. As a tool for screening and pinpointing potential TTCAs, we anticipate TTCA-IF to be invaluable in advancing cancer immunotherapy.
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Affiliation(s)
- Mir Tanveerul Hassan
- Department of Electronics and Information Engineering, Jeonbuk National University, Jeonju, 54896, South Korea
| | - Hilal Tayara
- School of International Engineering and Science, Jeonbuk National University, Jeonju, 54896, South Korea.
| | - Kil To Chong
- Department of Electronics and Information Engineering, Jeonbuk National University, Jeonju, 54896, South Korea; Advances Electronics and Information Research Centre, Jeonbuk National University, Jeonju, 54896, South Korea.
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14
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Ilangumaran S, Gui Y, Shukla A, Ramanathan S. SOCS1 expression in cancer cells: potential roles in promoting antitumor immunity. Front Immunol 2024; 15:1362224. [PMID: 38415248 PMCID: PMC10897024 DOI: 10.3389/fimmu.2024.1362224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 01/31/2024] [Indexed: 02/29/2024] Open
Abstract
Suppressor of cytokine signaling 1 (SOCS1) is a potent regulator immune cell responses and a proven tumor suppressor. Inhibition of SOCS1 in T cells can boost antitumor immunity, whereas its loss in tumor cells increases tumor aggressivity. Investigations into the tumor suppression mechanisms so far focused on tumor cell-intrinsic functions of SOCS1. However, it is possible that SOCS1 expression in tumor cells also regulate antitumor immune responses in a cell-extrinsic manner via direct and indirect mechanisms. Here, we discuss the evidence supporting the latter, and its implications for antitumor immunity.
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Affiliation(s)
- Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
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15
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Apavaloaei A, Perreault C. Immunotargeting of a recurrent AML-specific neoantigen. NATURE CANCER 2023; 4:1403-1405. [PMID: 37783806 DOI: 10.1038/s43018-023-00634-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
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16
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Al-Hawary SIS, Saleh EAM, Mamajanov NA, S Gilmanova N, Alsaab HO, Alghamdi A, Ansari SA, Alawady AHR, Alsaalamy AH, Ibrahim AJ. Breast cancer vaccines; A comprehensive and updated review. Pathol Res Pract 2023; 249:154735. [PMID: 37611432 DOI: 10.1016/j.prp.2023.154735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 07/30/2023] [Accepted: 08/02/2023] [Indexed: 08/25/2023]
Abstract
According to the International Agency for Research on Cancer, breast cancer is more common than lung cancer globally. By 2040, mortality from breast cancer will rise by 50% and 40%, respectively. Despite advances in chemotherapy, endocrine therapy, and HER2-targeted therapy, breast cancer metastases and recurrences remain challenging to treat. Cancer vaccines are an effective treatment option because they stimulate a long-lasting immune response that will eliminate tumor cells. In studies on the breast cancer vaccine, no appreciable advantages were discovered. A recent study claims that immune checkpoint inhibitors or anti-HER2 monoclonal antibodies may be used in vaccinations. This vaccination strengthens the immune system to fight off breast cancer cells. Clinical trials have been conducted on DNA, dendritic cells, and peptide-based breast cancer vaccines. Studies on the breast cancer vaccine have employed subcutaneous, intramuscular, and intradermal injections. Clinical studies have shown that these efforts have not been successful. Several factors might have slowed the development of a breast cancer vaccine. The complexity of the immune system makes it challenging to create cancer vaccines. Given the heterogeneity of breast cancer, there may be a need for different vaccination strategies. Despite these obstacles, research into breast cancer vaccines continues. Effective methods for creating vaccines include immune checkpoint inhibition and anti-HER2 monoclonal antibodies. Research is also being done on specialized tumor vaccinations.
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Affiliation(s)
| | - Ebraheem Abdu Musad Saleh
- Department of Chemistry, Prince Sattam Bin Abdulaziz University, College of Arts and Science, Wadi Al-Dawasir 11991, Saudi Arabia
| | - Nodirjon Akhmetovich Mamajanov
- Teaching Assistant, MD, Department of Public Health, Healthcare Management and Physical Culture, Tashkent State Dental Institute, Tashkent, Uzbekistan; Research scholar, Department of Scientific Affairs, Samarkand State Medical Institute, Samarkand, Uzbekistan
| | - Nataliya S Gilmanova
- Department of Prosthetic Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif 21944, Saudi Arabia
| | - Adel Alghamdi
- Preparatory Year Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
| | - Shakeel Ahmed Ansari
- Department of Biochemistry, General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
| | - Ahmed Hussien Radie Alawady
- College of technical engineering, the Islamic University, Najaf, Iraq; College of technical engineering, the Islamic University of Al Diwaniyah, Iraq; College of technical engineering, the Islamic University of Babylon, Iraq
| | - Ali Hashiem Alsaalamy
- College of technical engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
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17
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Herpels M, Ishihara J, Sadanandam A. The clinical terrain of immunotherapies in heterogeneous pancreatic cancer: unravelling challenges and opportunities. J Pathol 2023; 260:533-550. [PMID: 37550956 DOI: 10.1002/path.6171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 08/09/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer and has abysmal survival rates. In the past two decades, immunotherapeutic agents with success in other cancer types have gradually been trialled against PDACs at different stages of cancer progression, either as a monotherapy or in combination with chemotherapy. Unfortunately, to this day, chemotherapy still prolongs the survival rates the most and is prescribed in clinics despite the severe side effects in other cancer types. The low success rates of immunotherapy against PDAC have been attributed most frequently to its complex and multi-faceted tumour microenvironment (TME) and low mutational burden. In this review, we give a comprehensive overview of the immunotherapies tested in PDAC clinical trials thus far, their limitations, and potential explanations for their failure. We also discuss the existing classification of heterogenous PDACs into cancer, cancer-associated fibroblast, and immune subtypes and their potential opportunity in patient selection as a form of personalisation of PDAC immunotherapy. © 2023 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Melanie Herpels
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Department of Bioengineering, Imperial College London, London, UK
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, UK
| | - Anguraj Sadanandam
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Global Oncology, Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Translational Immunotherapy, Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
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18
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Peri A, Salomon N, Wolf Y, Kreiter S, Diken M, Samuels Y. The landscape of T cell antigens for cancer immunotherapy. NATURE CANCER 2023:10.1038/s43018-023-00588-x. [PMID: 37415076 DOI: 10.1038/s43018-023-00588-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 05/18/2023] [Indexed: 07/08/2023]
Abstract
The remarkable capacity of immunotherapies to induce durable regression in some patients with metastatic cancer relies heavily on T cell recognition of tumor-presented antigens. As checkpoint-blockade therapy has limited efficacy, tumor antigens have the potential to be exploited for complementary treatments, many of which are already in clinical trials. The surge of interest in this topic has led to the expansion of the tumor antigen landscape with the emergence of new antigen categories. Nonetheless, how different antigens compare in their ability to elicit efficient and safe clinical responses remains largely unknown. Here, we review known cancer peptide antigens, their attributes and the relevant clinical data and discuss future directions.
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Affiliation(s)
- Aviyah Peri
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Nadja Salomon
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany
| | - Yochai Wolf
- Ella Lemelbaum Institute for Immuno-oncology and Skin Cancer, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
- Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Sebastian Kreiter
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany.
| | - Mustafa Diken
- TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany.
| | - Yardena Samuels
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
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Rocha Pinheiro SL, Lemos FFB, Marques HS, Silva Luz M, de Oliveira Silva LG, Faria Souza Mendes dos Santos C, da Costa Evangelista K, Calmon MS, Sande Loureiro M, Freire de Melo F. Immunotherapy in glioblastoma treatment: Current state and future prospects. World J Clin Oncol 2023; 14:138-159. [PMID: 37124134 PMCID: PMC10134201 DOI: 10.5306/wjco.v14.i4.138] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/06/2023] [Accepted: 04/12/2023] [Indexed: 04/21/2023] Open
Abstract
Glioblastoma remains as the most common and aggressive malignant brain tumor, standing with a poor prognosis and treatment prospective. Despite the aggressive standard care, such as surgical resection and chemoradiation, median survival rates are low. In this regard, immunotherapeutic strategies aim to become more attractive for glioblastoma, considering its recent advances and approaches. In this review, we provide an overview of the current status and progress in immunotherapy for glioblastoma, going through the fundamental knowledge on immune targeting to promising strategies, such as Chimeric antigen receptor T-Cell therapy, immune checkpoint inhibitors, cytokine-based treatment, oncolytic virus and vaccine-based techniques. At last, it is discussed innovative methods to overcome diverse challenges, and future perspectives in this area.
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Affiliation(s)
- Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | | | | | - Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Obaidat D, Giordo R, Kleinbrink EL, Banisad E, Grossman LI, Arshad R, Stark A, Maroun MC, Lipovich L, Fernandez-Madrid F. Non-coding regions of nuclear-DNA-encoded mitochondrial genes and intergenic sequences are targeted by autoantibodies in breast cancer. Front Genet 2023; 13:970619. [PMID: 37082114 PMCID: PMC10111166 DOI: 10.3389/fgene.2022.970619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 11/15/2022] [Indexed: 03/31/2023] Open
Abstract
Autoantibodies against mitochondrial-derived antigens play a key role in chronic tissue inflammation in autoimmune disorders and cancers. Here, we identify autoreactive nuclear genomic DNA (nDNA)-encoded mitochondrial gene products (GAPDH, PKM2, GSTP1, SPATA5, MFF, TSPOAP1, PHB2, COA4, and HAGH) recognized by breast cancer (BC) patients’ sera as nonself, supporting a direct relationship of mitochondrial autoimmunity to breast carcinogenesis. Autoreactivity of multiple nDNA-encoded mitochondrial gene products was mapped to protein-coding regions, 3’ untranslated regions (UTRs), as well as introns. In addition, autoantibodies in BC sera targeted intergenic sequences that may be parts of long non-coding RNA (lncRNA) genes, including LINC02381 and other putative lncRNA neighbors of the protein-coding genes ERCC4, CXCL13, SOX3, PCDH1, EDDM3B, and GRB2. Increasing evidence indicates that lncRNAs play a key role in carcinogenesis. Consistent with this, our findings suggest that lncRNAs, as well as mRNAs of nDNA-encoded mitochondrial genes, mechanistically contribute to BC progression. This work supports a new paradigm of breast carcinogenesis based on a globally dysfunctional genome with altered function of multiple mitochondrial and non-mitochondrial oncogenic pathways caused by the effects of autoreactivity-induced dysregulation of multiple genes and their products. This autoimmunity-based model of carcinogenesis will open novel avenues for BC treatment.
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Affiliation(s)
- Deya Obaidat
- Department of Internal Medicine, Division of Rheumatology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Roberta Giordo
- Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Erica L. Kleinbrink
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States
- Quantitative Life Sciences, McGill University, Montreal, QC, Canada
| | - Emilia Banisad
- Department of Internal Medicine, Division of Rheumatology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Lawrence I. Grossman
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States
| | - Rooshan Arshad
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States
| | - Azadeh Stark
- Department of Pathology, Henry Ford Health System, Detroit, MI, United States
| | - Marie-Claire Maroun
- Department of Internal Medicine, Division of Rheumatology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Leonard Lipovich
- Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Shenzhen Huayuan Biotechnology Co. Ltd, Shenzhen Huayuan Biological Science Research Institute, Shenzhen, Guangdong, China
- *Correspondence: Leonard Lipovich, ; Félix Fernandez-Madrid,
| | - Félix Fernandez-Madrid
- Department of Internal Medicine, Division of Rheumatology, Wayne State University School of Medicine, Detroit, MI, United States
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States
- Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
- *Correspondence: Leonard Lipovich, ; Félix Fernandez-Madrid,
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Neoantigens: promising targets for cancer therapy. Signal Transduct Target Ther 2023; 8:9. [PMID: 36604431 PMCID: PMC9816309 DOI: 10.1038/s41392-022-01270-x] [Citation(s) in RCA: 360] [Impact Index Per Article: 180.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/14/2022] [Accepted: 11/27/2022] [Indexed: 01/07/2023] Open
Abstract
Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy and antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations, such as genomic mutation, dysregulated RNA splicing, disordered post-translational modification, and integrated viral open reading frames. Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance. The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies. Compared to tumor-associated antigens, the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies, and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses. The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies. This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens. We also explore their current status, inherent challenges, and clinical translation potential.
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22
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Zaman R, Islam RA, Chowdhury EH. Evolving therapeutic proteins to precisely kill cancer cells. J Control Release 2022; 351:779-804. [DOI: 10.1016/j.jconrel.2022.09.066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/27/2022] [Accepted: 09/29/2022] [Indexed: 10/31/2022]
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Wang ZL, Huang RY, Han B, Wu F, Sun ZY, Li GZ, Zhang W, Zhao Z, Liu X. Identification of tumor-associated antigens and immune subtypes of lower-grade glioma and glioblastoma for mRNA vaccine development. Chin Neurosurg J 2022; 8:34. [PMID: 36307882 PMCID: PMC9614757 DOI: 10.1186/s41016-022-00301-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 09/21/2022] [Indexed: 11/06/2022] Open
Abstract
Background mRNA became a promising therapeutic approach in many diseases. This study aimed to identify the tumor antigens specifically expressed in tumor cells for lower-grade glioma (LGG) and glioblastoma (GBM) patients. Methods In this work, the mRNA microarray expression profile and clinical data were obtained from 301 samples in the Chinese Glioma Genome Atlas (CGGA) database, the mRNA sequencing data and clinical data of 701 samples were downloaded from The Cancer Genome Atlas (TCGA) database. Genetic alterations profiles were extracted from CGGA and cBioPortal datasets. R language and GraphPad Prism software were applied for the statistical analysis and graph work. Results PTBP1 and SLC39A1, which were overexpressed and indicated poor prognosis in LGG patients, were selected as tumor-specific antigens for LGG patients. Meanwhile, MMP9 and SLC16A3, the negative prognostic factors overexpressed in GBM, were identified as tumor-specific antigens for GBM patients. Besides, three immune subtypes (LGG1-LGG3) and eight WGCNA modules were identified in LGG patients. Meanwhile, two immune subtypes (GBM1–GBM2) and 10 WGCNA modules were selected in GBM. The immune characteristics and potential functions between different subtypes were diversity. LGG2 and GBM1 immune subtype were associated with longer overall survival than other subtypes. Conclusion In this study, PTBP1 and SLC39A1 are promising antigens for mRNA vaccines development in LGG, and MMP9 and SLC16A3 were potential antigens in GBM. Our analyses indicated that mRNA vaccine immunotherapy was more suitable for LGG2 and GBM1 subtypes. This study was helpful for the development of glioma immunotherapies. Supplementary Information The online version contains supplementary material available at 10.1186/s41016-022-00301-4.
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Affiliation(s)
- Zhi-liang Wang
- grid.411617.40000 0004 0642 1244Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Ruo-yu Huang
- grid.411617.40000 0004 0642 1244Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 South 4th Ring West Road, Beijing, 100070 People’s Republic of China
| | - Bo Han
- grid.411617.40000 0004 0642 1244Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Fan Wu
- grid.411617.40000 0004 0642 1244Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 South 4th Ring West Road, Beijing, 100070 People’s Republic of China
| | - Zhi-yan Sun
- grid.411617.40000 0004 0642 1244Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 South 4th Ring West Road, Beijing, 100070 People’s Republic of China
| | - Guan-zhang Li
- grid.411617.40000 0004 0642 1244Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 South 4th Ring West Road, Beijing, 100070 People’s Republic of China
| | - Wei Zhang
- grid.411617.40000 0004 0642 1244Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Zheng Zhao
- grid.411617.40000 0004 0642 1244Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 South 4th Ring West Road, Beijing, 100070 People’s Republic of China
| | - Xing Liu
- grid.411617.40000 0004 0642 1244Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, No. 119 South 4th Ring West Road, Beijing, 100070 People’s Republic of China
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24
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Apavaloaei A, Hesnard L, Hardy MP, Benabdallah B, Ehx G, Thériault C, Laverdure JP, Durette C, Lanoix J, Courcelles M, Noronha N, Chauhan KD, Lemieux S, Beauséjour C, Bhatia M, Thibault P, Perreault C. Induced pluripotent stem cells display a distinct set of MHC I-associated peptides shared by human cancers. Cell Rep 2022; 40:111241. [PMID: 35977509 DOI: 10.1016/j.celrep.2022.111241] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 06/20/2022] [Accepted: 07/27/2022] [Indexed: 11/03/2022] Open
Abstract
Previous reports showed that mouse vaccination with pluripotent stem cells (PSCs) induces durable anti-tumor immune responses via T cell recognition of some elusive oncofetal epitopes. We characterize the MHC I-associated peptide (MAP) repertoire of human induced PSCs (iPSCs) using proteogenomics. Our analyses reveal a set of 46 pluripotency-associated MAPs (paMAPs) absent from the transcriptome of normal tissues and adult stem cells but expressed in PSCs and multiple adult cancers. These paMAPs derive from coding and allegedly non-coding (48%) transcripts involved in pluripotency maintenance, and their expression in The Cancer Genome Atlas samples correlates with source gene hypomethylation and genomic aberrations common across cancer types. We find that several of these paMAPs were immunogenic. However, paMAP expression in tumors coincides with activation of pathways instrumental in immune evasion (WNT, TGF-β, and CDK4/6). We propose that currently available inhibitors of these pathways could synergize with immune targeting of paMAPs for the treatment of poorly differentiated cancers.
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Affiliation(s)
- Anca Apavaloaei
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Leslie Hesnard
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Marie-Pierre Hardy
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | | | - Gregory Ehx
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Catherine Thériault
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Jean-Philippe Laverdure
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Chantal Durette
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Joël Lanoix
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Mathieu Courcelles
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Nandita Noronha
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Kapil Dev Chauhan
- Faculty of Health Sciences, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Sébastien Lemieux
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada; Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Christian Beauséjour
- CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pharmacology and Physiology, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Mick Bhatia
- Faculty of Health Sciences, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Pierre Thibault
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada; Department of Chemistry, University of Montreal, Montreal, QC H3T 1J4, Canada.
| | - Claude Perreault
- Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada; Department of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada.
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25
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Xu S, Wang X, Fei C. A Highly Effective System for Predicting MHC-II Epitopes With Immunogenicity. Front Oncol 2022; 12:888556. [PMID: 35785204 PMCID: PMC9246415 DOI: 10.3389/fonc.2022.888556] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/27/2022] [Indexed: 12/30/2022] Open
Abstract
In the past decade, the substantial achievements of therapeutic cancer vaccines have shed a new light on cancer immunotherapy. The major challenge for designing potent therapeutic cancer vaccines is to identify neoantigens capable of inducing sufficient immune responses, especially involving major histocompatibility complex (MHC)-II epitopes. However, most previous studies on T-cell epitopes were focused on either ligand binding or antigen presentation by MHC rather than the immunogenicity of T-cell epitopes. In order to better facilitate a therapeutic vaccine design, in this study, we propose a revolutionary new tool: a convolutional neural network model named FIONA (Flexible Immunogenicity Optimization Neural-network Architecture) trained on IEDB datasets. FIONA could accurately predict the epitopes presented by the given specific MHC-II subtypes, as well as their immunogenicity. By leveraging the human leukocyte antigen allele hierarchical encoding model together with peptide dense embedding fusion encoding, FIONA (with AUC = 0.94) outperforms several other tools in predicting epitopes presented by MHC-II subtypes in head-to-head comparison; moreover, FIONA has unprecedentedly incorporated the capacity to predict the immunogenicity of epitopes with MHC-II subtype specificity. Therefore, we developed a reliable pipeline to effectively predict CD4+ T-cell immune responses against cancer and infectious diseases.
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Affiliation(s)
| | | | - Caiyi Fei
- Department of AI and Bioinformatics, Nanjing Chengshi BioTech (TheraRNA) Co., Ltd., Nanjing, China
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26
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Ottaviani A, Welsch J, Agama K, Pommier Y, Desideri A, Baker BJ, Fiorani P. From Antarctica to cancer research: a novel human DNA topoisomerase 1B inhibitor from Antarctic sponge Dendrilla antarctica. J Enzyme Inhib Med Chem 2022; 37:1404-1410. [PMID: 35603503 PMCID: PMC9132426 DOI: 10.1080/14756366.2022.2078320] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Nature has been always a great source of possible lead compounds to develop new drugs against several diseases. Here we report the identification of a natural compound, membranoid G, derived from the Antarctic sponge Dendrilla antarctica displaying an in vitro inhibitory activity against human DNA topoisomerase 1B. The experiments indicate that membranoid G, when pre-incubated with the enzyme, strongly and irreversibly inhibits the relaxation of supercoiled DNA. This compound completely inhibits the cleavage step of the enzyme catalytic mechanism by preventing protein binding to the DNA. Membranoid G displays also a cytotoxic effect on tumour cell lines, suggesting its use as a possible lead compound to develop new anticancer drugs.
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Affiliation(s)
| | - Joshua Welsch
- Department of Chemistry, University of South Florida, Tampa, FL, USA
| | - Keli Agama
- Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Yves Pommier
- Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | - Bill J. Baker
- Department of Chemistry, University of South Florida, Tampa, FL, USA
| | - Paola Fiorani
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- Institute of Translational Pharmacology, National Research Council, CNR, Rome, Italy
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27
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Li H, Yu Z, Wang H, Wang N, Sun X, Yang S, Hua X, Liu Z. Role of ANO1 in tumors and tumor immunity. J Cancer Res Clin Oncol 2022; 148:2045-2068. [PMID: 35471604 DOI: 10.1007/s00432-022-04004-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 03/29/2022] [Indexed: 12/24/2022]
Abstract
Dysregulation of gene amplification, cell-signaling-pathway transduction, epigenetic and transcriptional regulation, and protein interactions drives tumor-cell proliferation and invasion, while ion channels also play an important role in the generation and development of tumor cells. Overexpression of Ca2+-activated Cl- channel anoctamin 1 (ANO1) is shown in numerous cancer types and correlates with poor prognosis. However, the mechanisms involved in ANO1-mediated malignant cellular transformation and the role of ANO1 in tumor immunity remain unknown. In this review, we discuss recent studies to determine the role of ANO1 in tumorigenesis and provide novel insights into the role of ANO1 in the context of tumor immunity. Furthermore, we analyze the roles and potential mechanisms of ANO1 in different types of cancers, and provide novel notions for the role of ANO1 in the tumor microenvironment and for potential use of ANO1 in clinical applications. Our review shows that ANO1 is involved in tumor immunity and microenvironment, and may, therefore, be an effective biomarker and therapeutic drug target.
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Affiliation(s)
- Haini Li
- Department of Gastroenterology, Qingdao Sixth People's Hospital, Qingdao, 266001, China
| | - Zongxue Yu
- Department of Endocrinology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266001, China
| | - Haiyan Wang
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China
| | - Ning Wang
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China
| | - Xueguo Sun
- Department of Gastroenterology, Qingdao University Affiliated Hospital, Qingdao, 266001, China
| | - Shengmei Yang
- Department of Gynecology, Qingdao University Affiliated Hospital, Qingdao, 266001, China
| | - Xu Hua
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China
| | - Zongtao Liu
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China.
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28
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Wang Y, Zhang R, Tang L, Yang L. Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy. Pharmaceutics 2022; 14:512. [PMID: 35335891 PMCID: PMC8949480 DOI: 10.3390/pharmaceutics14030512] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/12/2022] [Accepted: 02/23/2022] [Indexed: 01/14/2023] Open
Abstract
In recent years, the use of messenger RNA (mRNA) in the fields of gene therapy, immunotherapy, and stem cell biomedicine has received extensive attention. With the development of scientific technology, mRNA applications for tumor treatment have matured. Since the SARS-CoV-2 infection outbreak in 2019, the development of engineered mRNA and mRNA vaccines has accelerated rapidly. mRNA is easy to produce, scalable, modifiable, and not integrated into the host genome, showing tremendous potential for cancer gene therapy and immunotherapy when used in combination with traditional strategies. The core mechanism of mRNA therapy is vehicle-based delivery of in vitro transcribed mRNA (IVT mRNA), which is large, negatively charged, and easily degradable, into the cytoplasm and subsequent expression of the corresponding proteins. However, effectively delivering mRNA into cells and successfully activating the immune response are the keys to the clinical transformation of mRNA therapy. In this review, we focus on nonviral nanodelivery systems of mRNA vaccines used for cancer gene therapy and immunotherapy.
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Affiliation(s)
| | | | | | - Li Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.W.); (R.Z.); (L.T.)
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29
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Kroemer G, Galassi C, Zitvogel L, Galluzzi L. Immunogenic cell stress and death. Nat Immunol 2022; 23:487-500. [PMID: 35145297 DOI: 10.1038/s41590-022-01132-2] [Citation(s) in RCA: 656] [Impact Index Per Article: 218.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 01/07/2022] [Indexed: 12/20/2022]
Abstract
Dying mammalian cells emit numerous signals that interact with the host to dictate the immunological correlates of cellular stress and death. In the absence of reactive antigenic determinants (which is generally the case for healthy cells), such signals may drive inflammation but cannot engage adaptive immunity. Conversely, when cells exhibit sufficient antigenicity, as in the case of infected or malignant cells, their death can culminate with adaptive immune responses that are executed by cytotoxic T lymphocytes and elicit immunological memory. Suggesting a key role for immunogenic cell death (ICD) in immunosurveillance, both pathogens and cancer cells evolved strategies to prevent the recognition of cell death as immunogenic. Intriguingly, normal cells succumbing to conditions that promote the formation of post-translational neoantigens (for example, oxidative stress) can also drive at least some degree of antigen-specific immunity, pointing to a novel implication of ICD in the etiology of non-infectious, non-malignant disorders linked to autoreactivity.
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Affiliation(s)
- Guido Kroemer
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université de Paris, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Laurence Zitvogel
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.,Université Paris Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France.,INSERM U1015, Villejuif, France.,Equipe labellisée par la Ligue contre le cancer, Villejuif, France.,Center of Clinical Investigations in Biotherapies of Cancer (CICBT) BIOTHERIS, Villejuif, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. .,Sandra and Edward Meyer Cancer Center, New York, NY, USA. .,Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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30
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Zitvogel L, Perreault C, Finn OJ, Kroemer G. Beneficial autoimmunity improves cancer prognosis. Nat Rev Clin Oncol 2021; 18:591-602. [PMID: 33976418 DOI: 10.1038/s41571-021-00508-x] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2021] [Indexed: 02/06/2023]
Abstract
Many tumour antigens that do not arise from cancer cell-specific mutations are targets of humoral and cellular immunity despite their expression on non-malignant cells. Thus, in addition to the expected ability to detect mutations and stress-associated shifts in the immunoproteome and immunopeptidome (the sum of MHC class I-bound peptides) unique to malignant cells, the immune system also recognizes antigens expressed in non-malignant cells, which can result in autoimmune reactions against non-malignant cells from the tissue of origin. These autoimmune manifestations include, among others, vitiligo, thyroiditis and paraneoplastic syndromes, concurrent with melanoma, thyroid cancer and non-small-cell lung cancer, respectively. Importantly, despite the undesirable effects of these symptoms, such events can have prognostic value and correlate with favourable disease outcomes, suggesting 'beneficial autoimmunity'. Similarly, the occurrence of dermal and endocrine autoimmune adverse events in patients receiving immune-checkpoint inhibitors can have a positive predictive value for therapeutic outcomes. Neoplasias derived from stem cells deemed 'not essential' for survival (such as melanocytes, thyroid cells and most cells in sex-specific organs) have a particularly good prognosis, perhaps because the host can tolerate autoimmune reactions that destroy tumour cells at some cost to non-malignant tissues. In this Perspective, we discuss examples of spontaneous as well as therapy-induced autoimmunity that correlate with favourable disease outcomes and make a strong case in favour of this 'beneficial autoimmunity' being important not only in patients with advanced-stage disease but also in cancer immunosurveillance.
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Affiliation(s)
- Laurence Zitvogel
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. .,Université Paris Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France. .,INSERM U1015, Gustave Roussy, Villejuif, France. .,Equipe labellisée par la Ligue contre le cancer, Villejuif, France. .,Center of Clinical Investigations in Biotherapies of Cancer (CICBT) BIOTHERIS, Villejuif, France. .,Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
| | - Claude Perreault
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada
| | - Olivera J Finn
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Guido Kroemer
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. .,Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China. .,Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. .,Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
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31
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Shklovskaya E, Rizos H. MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It. Int J Mol Sci 2021; 22:ijms22136741. [PMID: 34201655 PMCID: PMC8268865 DOI: 10.3390/ijms22136741] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 12/21/2022] Open
Abstract
It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.
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32
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β-Glucan: A dual regulator of apoptosis and cell proliferation. Int J Biol Macromol 2021; 182:1229-1237. [PMID: 33991557 DOI: 10.1016/j.ijbiomac.2021.05.065] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/26/2021] [Accepted: 05/10/2021] [Indexed: 01/09/2023]
Abstract
β-Glucans are polysaccharides generally obtained from the cell wall of bacteria, fungi, yeasts, and aleurone layer of cereals. β-Glucans are polymers, with β-1,3 glucose as core linear structure, but they differ in their main branch length, linkages and branching patterns, giving rise to high and low-molecular-weight β-glucans. They are well-known cell response modifiers with immune-modulating, nutraceutical and health beneficial effects, including anticancer and pro-apoptotic properties. β-Glucan extracts have shown positive responses in controlling tumor cell proliferation and activation of the immune system. The immunomodulatory action of β-glucans enhances the host's antitumor defense against cancer. In consonance with the above, many studies have shown that β-glucan treatment leads to the induction of apoptotic death of cancer cells. The ability of β-glucans to stimulate apoptotic pathways or the proteins involved in apoptosis prompting a new domain in cancer therapy. β-glucan can be a potential therapeutic agent for the treatment of cancer. However, there is a need to legitimize the β-glucan type, as most of the studies include β-glucan from different sources having different physicochemical properties. The body of literature presented here focuses on the effects of β-glucan on immunomodulation, proliferation, cell death and the possible mechanisms and pathways involved in these processes.
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33
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Slaney CY, Kershaw MH. Challenges and Opportunities for Effective Cancer Immunotherapies. Cancers (Basel) 2020; 12:E3164. [PMID: 33126513 PMCID: PMC7693360 DOI: 10.3390/cancers12113164] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 10/24/2020] [Indexed: 12/14/2022] Open
Abstract
Using immunotherapy to treat cancers can be traced back to the 1890s, where a New York physician William Coley used heat-killed bacteria to treat cancer patients, which became known as "Coley's toxin" [...].
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Affiliation(s)
- Clare Y. Slaney
- Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria 3000, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3000, Australia
| | - Michael H. Kershaw
- Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria 3000, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3000, Australia
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