1
|
Ge Y, Jiang L, Dong Q, Xu Y, Yam JWP, Zhong X. Exosome-mediated Crosstalk in the Tumor Immune Microenvironment: Critical Drivers of Hepatocellular Carcinoma Progression. J Clin Transl Hepatol 2025; 13:143-161. [PMID: 39917466 PMCID: PMC11797817 DOI: 10.14218/jcth.2024.00302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 02/09/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant global health issue, ranking as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, mortality rates for HCC remain high. The tumor immune microenvironment (TIME) plays a vital role in HCC progression by influencing tumor cell survival and growth. Recent studies highlight the essential role of exosomes in mediating intercellular communication within the TIME, particularly in interactions among tumor cells, immune cells, and fibroblasts. These interactions drive critical aspects of tumor development, including immune escape, angiogenesis, drug resistance, and metastasis. A detailed understanding of the molecular mechanisms by which exosomes modulate the TIME is essential for developing targeted therapies. This review systematically evaluated the roles and regulatory mechanisms of exosomes within the TIME of HCC, examining the impact of both HCC-derived and non-HCC-derived exosomes on various cellular components within the TIME. It emphasized their regulatory effects on cell phenotypes and functions, as well as their roles in HCC progression. The review also explored the potential applications of exosome-based immunotherapies, offering new insights into improving therapeutic strategies for HCC.
Collapse
Affiliation(s)
- Yifei Ge
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lixue Jiang
- Department of Breast Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Qingfu Dong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian, China
- Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xiangyu Zhong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| |
Collapse
|
2
|
Liu X, To KKW, Zeng Q, Fu L. Effect of Extracellular Vesicles Derived From Tumor Cells on Immune Evasion. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2417357. [PMID: 39899680 DOI: 10.1002/advs.202417357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Indexed: 02/05/2025]
Abstract
The crosstalk between immunity and cancer in the regulation of tumor growth is considered a hallmark of cancer. Antitumor immunity refers to the innate and adaptive immune responses that regulate cancer development and proliferation. Tumor immune evasion represents a major hindrance to effective anticancer treatment. Extracellular vesicles (EVs) are nano-sized and lipid-bilayer-enclosed particles that are secreted to the extracellular space by all cell types. They are critically involved in numerous biological functions including intercellular communication. Tumor-derived extracellular vesicles (TEVs) can transport a variety of cargo to modulate immune cells in the tumor microenvironment (TME). This review provides the latest update about how tumor cells evade immune surveillance by exploiting TEVs. First, the biogenesis of EVs and the cargo-sorting machinery are discussed. Second, how tumor cells modulate immune cell differentiation, activation, and function via TEVs to evade immune surveillance is illustrated. Last but not least, the novel antitumor strategies that can reverse immune escape are summarized.
Collapse
Affiliation(s)
- Xuanfan Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P. R. China
| | - Kenneth K W To
- School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, 999077, P. R. China
| | - Qinsong Zeng
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P. R. China
- Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, 530025, P. R. China
| | - Liwu Fu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| |
Collapse
|
3
|
Nie L, Ma J, Yu Y, Tao Y, Song Z, Li J. Exosomes as carriers to stimulate an anti-cancer immune response in immunotherapy and as predictive markers. Biochem Pharmacol 2025; 232:116699. [PMID: 39647605 DOI: 10.1016/j.bcp.2024.116699] [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: 09/29/2024] [Revised: 11/26/2024] [Accepted: 12/03/2024] [Indexed: 12/10/2024]
Abstract
During this era of rapid advancements in cancer immunotherapy, the application of cell-released small vesicles that activate the immune system is of considerable interest. Exosomes are cell-derived nanovesicles that show great promise for the immunological treatment of cancer because of their immunogenicity and molecular transfer capacity. Recent technological advancements have enabled the identification of functional functions that exosome cargoes perform in controlling immune responses. Exosomes are originated specifically from immune cells and tumor cells and they show unique composition patterns directly related to the immunotherapy against cancer. Exosomes can also deliver their cargo to particular cells, which can affect the phenotypic and immune-regulatory functions of those cells. Exosomes can influence the course of cancer and have therapeutic benefits by taking part in several cellular processes; as a result, they have the dual properties of activating and restraining cancer. Exosomes have tremendous potential for cancer immunotherapy; they may develop into the most powerful cancer vaccines and carriers of targeted antigens and drugs. Comprehending the potential applications of exosomes in immune therapy is significant for regulating cancer progression. This review offers an analysis of the function of exosomes in immunotherapy, specifically as carriers that function as diagnostic indicators for immunological activation and trigger an anti-cancer immune response. Moreover, it summarizes the fundamental mechanism and possible therapeutic applications of exosome-based immunotherapy for human cancer.
Collapse
Affiliation(s)
- Lili Nie
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, China
| | - Jingru Ma
- Department of Clinical Laboratory, the Second Hospital of Jilin University, Changchun, China
| | - Yang Yu
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun, China
| | - Ying Tao
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhidu Song
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, China
| | - Jian Li
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun, China.
| |
Collapse
|
4
|
Ahuja S, Zaheer S. The evolution of cancer immunotherapy: a comprehensive review of its history and current perspectives. KOREAN JOURNAL OF CLINICAL ONCOLOGY 2024; 20:51-73. [PMID: 39778508 PMCID: PMC11717579 DOI: 10.14216/kjco.24009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/24/2024] [Accepted: 11/19/2024] [Indexed: 01/11/2025]
Abstract
Cancer immunotherapy uses the body's immune system to combat cancer, marking a significant advancement in treatment. This review traces its evolution from the late 19th century to its current status. It began with William Coley's pioneering work using bacterial toxins to stimulate the immune system against cancer cells, establishing the foundational concept of immunotherapy. In the mid-20th century, cytokine therapies like interferons and interleukins emerged, demonstrating that altering the immune response could reduce tumors and highlighting the complex interplay between cancer and the immune system. The discovery of immune checkpoints, regulatory pathways that prevent autoimmunity but are exploited by cancer cells to evade detection, was a pivotal development. Another major breakthrough is CAR-T cell therapy, which involves modifying a patient's T cells to target cancer-specific antigens. This personalized treatment has shown remarkable success in certain blood cancers. Additionally, cancer vaccines aim to trigger immune responses against tumor-specific or associated antigens, and while challenging, ongoing research is improving their efficacy. The historical progression of cancer immunotherapy, from Coley's toxins to modern innovations like checkpoint inhibitors and CAR-T cell therapy, underscores its transformative impact on cancer treatment. As research delves deeper into the immune system's complexities, immunotherapy is poised to become even more crucial in oncology, offering renewed hope to patients globally.
Collapse
Affiliation(s)
- Sana Ahuja
- Department of Pathology, Safdarjung Hospital, Vardhman Mahavir Medical College, New Delhi, India
| | - Sufian Zaheer
- Department of Pathology, Safdarjung Hospital, Vardhman Mahavir Medical College, New Delhi, India
| |
Collapse
|
5
|
Greppi M, De Franco F, Obino V, Rebaudi F, Goda R, Frumento D, Vita G, Baronti C, Melaiu O, Bozzo M, Candiani S, Vellone VG, Papaccio F, Pesce S, Marcenaro E. NK cell receptors in anti-tumor and healthy tissue protection: Mechanisms and therapeutic advances. Immunol Lett 2024; 270:106932. [PMID: 39303993 DOI: 10.1016/j.imlet.2024.106932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/10/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
Natural Killer (NK) cells are integral to the innate immune system, renowned for their ability to target and eliminate cancer cells without the need for antigen presentation, sparing normal tissues. These cells are crucial in cancer immunosurveillance due to their diverse array of activating and inhibitory receptors that modulate their cytotoxic activity. However, the tumor microenvironment can suppress NK cell function through various mechanisms. Over recent decades, research has focused on overcoming these tumor escape mechanisms. Initially, efforts concentrated on enhancing T cell activity, leading to impressive results with immunotherapeutic approaches aimed at boosting T cell responses. Nevertheless, a substantial number of patients do not benefit from these treatments and continue to seek effective alternatives. In this context, NK cells present a promising avenue for developing new treatments, given their potent cytotoxic capabilities, safety profile, and activity against T cell-resistant tumors, such as those lacking HLA-I expression. Recent advancements in immunotherapy include strategies to restore and amplify NK cell activity through immune checkpoint inhibitors, cytokines, adoptive NK cell therapy, and CAR-NK cell technology. This review provides a comprehensive overview of NK cell receptors, the tumor escape mechanisms that hinder NK cell function, and the evolving field of NK cell-based cancer immunotherapy, highlighting ongoing efforts to develop more effective and targeted cancer treatment strategies.
Collapse
Affiliation(s)
- Marco Greppi
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Fabiana De Franco
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Valentina Obino
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Federico Rebaudi
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Rayan Goda
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Davide Frumento
- Department of Education Sciences, University of Rome Tre, Rome, Italy
| | - Giorgio Vita
- Department of Internal Medicine (DIMI), University of Genoa, Genoa, Italy
| | - Camilla Baronti
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Ombretta Melaiu
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Matteo Bozzo
- Department of Earth, Environmental and Life Sciences (DISTAV), University of Genoa, Genoa, Italy
| | - Simona Candiani
- Department of Earth, Environmental and Life Sciences (DISTAV), University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Valerio G Vellone
- Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy; Pathology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Federica Papaccio
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Baronissi, Italy.
| | - Silvia Pesce
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy.
| | - Emanuela Marcenaro
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy.
| |
Collapse
|
6
|
Littera R, Mocci S, Argiolas D, Littarru L, Lai S, Melis M, Sanna C, Mereu C, Lorrai M, Mascia A, Angioi A, Mascia G, Matta V, Lepori N, Floris M, Manieli C, Bianco P, Onnis D, Rassu S, Deidda S, Carta MG, Giuressi E, Perra A, Chessa L, Giglio S, Pani A. MICA and NKG2D gene polymorphisms influence graft survival, and response to therapy in kidney transplantation. Front Immunol 2024; 15:1440887. [PMID: 39575256 PMCID: PMC11578996 DOI: 10.3389/fimmu.2024.1440887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 10/18/2024] [Indexed: 11/24/2024] Open
Abstract
Background Antibody-mediated rejection is a significant cause of kidney transplant failure. Recent studies have shown that the MHC class I MICA gene influences the transplantation outcome. However, the role of the primary MICA receptor, NKG2D, has yet to be explored. Aim We aimed to investigate the correlation between recipient/donor MICA allele matching and NKG2D genotype with the risk of antibody-mediated rejection and their potential clinical effects and implications for organ maintenance therapy. Methods Of the 524 patients who underwent transplantation, 387 were eligible for the study. Complete MICA allele and two functional polymorphisms of NKG2D (rs1049174C>G and rs2255336G>A) were analyzed in 148 transplanted patients and 146 controls. Results Increased recipient/donor MICA allele mismatches correlate with an elevated risk of antibody-mediated rejection (X2 = 6.95; Log-rank=0.031). Notably, the rs1049174[GG] genotype contributes to a significantly increased risk of antibody-mediated rejection (X2 = 13.44; Log-rank=0.001 and X 2 = 0.34; Log-rank=0.84). The combined effect of two MICA allele mismatches and rs1049174[GG] genotype shows the highest risk (X2 = 23.21; Log-rank<0.001). Most importantly, patients with rs1049174[GG] and rs2255336[AA] genotypes may respond less to mTOR inhibitor immunosuppressive therapy than Calcineurin inhibitors (rs1049174[GG]; P=0.035; and rs2255336[AA]; P=0.002). Conclusion Recipient/donor MICA allele mismatches and specific NKG2D variants, as well as their combinations, influence kidney transplant outcomes, providing insights for personalized treatment and enhancing graft survival.
Collapse
Affiliation(s)
- Roberto Littera
- Medical Genetics, R. Binaghi Hospital, Cagliari, Italy
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
| | - Stefano Mocci
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Oncology and Molecular Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
- Center for Research University Services (CeSAR), (Centro Servizi di Ateneo per la Ricerca), University of Cagliari, Monserrato, Italy
| | - Davide Argiolas
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Letizia Littarru
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Sara Lai
- Medical Genetics, R. Binaghi Hospital, Cagliari, Italy
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
| | - Maurizio Melis
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
| | - Celeste Sanna
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Caterina Mereu
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Michela Lorrai
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Alessia Mascia
- Oncology and Molecular Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Andrea Angioi
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Giacomo Mascia
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Valeria Matta
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Nicola Lepori
- Department of Medical Science and Public Health, University of Cagliari, Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Matteo Floris
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
| | - Cristina Manieli
- U.O. Anatomia Patologica, P.O. San Michele, ARNAS “G Brotzu”, Cagliari, Italy
| | - Paola Bianco
- U.O. Anatomia Patologica, P.O. San Michele, ARNAS “G Brotzu”, Cagliari, Italy
| | - Daniela Onnis
- U.O. Anatomia Patologica, P.O. San Michele, ARNAS “G Brotzu”, Cagliari, Italy
| | | | - Silvia Deidda
- Pneumology Unit, R. Binaghi Hospital, ASSL Cagliari, Cagliari, Italy
| | - Mauro Giovanni Carta
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | | | - Andrea Perra
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
- Oncology and Molecular Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Luchino Chessa
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Liver Unit, Department of Internal Medicine, University Hospital of Cagliari, Cagliari, Italy
| | - Sabrina Giglio
- Medical Genetics, R. Binaghi Hospital, Cagliari, Italy
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Center for Research University Services (CeSAR), (Centro Servizi di Ateneo per la Ricerca), University of Cagliari, Monserrato, Italy
| | - Antonello Pani
- Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu”, Cagliari, Italy
- Department of Medical Science and Public Health, University of Cagliari, Nephrology, Dialysis and Transplantation Unit, ARNAS “G. Brotzu” Cagliari, Consiglio Nazionale delle Ricerche, Cagliari, Italy
| |
Collapse
|
7
|
Zhang SH, Peng LL, Chen YF, Xu Y, Moradi V. Focusing on exosomes to overcome the existing bottlenecks of CAR-T cell therapy. Inflamm Regen 2024; 44:45. [PMID: 39490997 PMCID: PMC11533312 DOI: 10.1186/s41232-024-00358-x] [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: 07/15/2024] [Accepted: 10/22/2024] [Indexed: 11/05/2024] Open
Abstract
Since chimeric antigen receptor T (CAR-T) cells were introduced three decades ago, the treatment using these cells has led to outstanding outcomes, and at the moment, CAR-T cell therapy is a well-established mainstay for treating CD19 + malignancies and multiple myeloma. Despite the astonishing results of CAR-T cell therapy in B-cell-derived malignancies, several bottlenecks must be overcome to promote its safety and efficacy and broaden its applicability. These bottlenecks include cumbersome production process, safety concerns of viral vectors, poor efficacy in treating solid tumors, life-threatening side effects, and dysfunctionality of infused CAR-T cells over time. Exosomes are nano-sized vesicles that are secreted by all living cells and play an essential role in cellular crosstalk by bridging between cells. In this review, we discuss how the existing bottlenecks of CAR-T cell therapy can be overcome by focusing on exosomes. First, we delve into the effect of tumor-derived exosomes on the CAR-T cell function and discuss how inhibiting their secretion can enhance the efficacy of CAR-T cell therapy. Afterward, the application of exosomes to the manufacturing of CAR-T cells in a non-viral approach is discussed. We also review the latest advancements in ex vivo activation and cultivation of CAR-T cells using exosomes, as well as the potential of engineered exosomes to in vivo induction or boost the in vivo proliferation of CAR-T cells. Finally, we discuss how CAR-engineered exosomes can be used as a versatile tool for the direct killing of tumor cells or delivering intended therapeutic payloads in a targeted manner.
Collapse
Affiliation(s)
- Si-Heng Zhang
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR, 999078, China
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310000, China
| | - Ling-Long Peng
- Wuhu Hospital, East China Normal University (The Second People's Hospital of Wuhu), Wuhu, 241000, China
| | - Yi-Fei Chen
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR, 999078, China
| | - Yan Xu
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310000, China.
| | - Vahid Moradi
- Hematology and Bood Transfusion Science Department, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
8
|
de Oliveira Ciriaco VA, Rodrigues AM, da Silva Tibúrcio BC, Silva JM, Naslavsky MS, Mendes-Junior CT, Bannwart Castro CF, Castelli EC. The MICA deletion across different populations. Hum Immunol 2024; 85:111183. [PMID: 39571451 DOI: 10.1016/j.humimm.2024.111183] [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: 06/04/2024] [Revised: 10/25/2024] [Accepted: 11/10/2024] [Indexed: 12/14/2024]
Abstract
The MICA gene encodes a glycoprotein upregulated upon cellular stress, particularly in oxidative stress, intracellular infections, and tumorigenesis. This stress-signaling molecule interacts with the activating receptor NKG2D from Natural Killer (NK) and some T lymphocytes, stimulating their cytotoxic activity. MICA is encoded within the human Major Histocompatibility Complex next to the HLA-B locus and is highly polymorphic. MICA might be absent from chromosome 6 due to a large deletion of approximately 100 Kb between HLA-B and MICB. Therefore, some individuals may not produce any isoform of MICA. The distribution of this phenotype may vary among different populations. We evaluated the distribution of the MICA*del and other MICA null alleles in different biogeographic regions and the Linkage Disequilibrium (LD) pattern between this allele and HLA-B. We detected at least two different patterns of deletion, one with full deletion of MICA and surrounding sequences and one partial MICA deletion. The presence of different patterns of deletion suggests independent deletion events. We confirm that the previously described MICA*del allele is mainly associated with B*48 and MICB*009N in Asia and America, but other haplotypes also occur. While most samples with complete or partial MICA deletion are heterozygous and present one functional copy of both MICA and MICB genes, we detected two samples with no functional MICA and one with no functional MIC genes. Therefore, other mechanisms might be in place to compensate for the absence of MIC molecules.
Collapse
Affiliation(s)
| | - Amanda Muniz Rodrigues
- São Paulo State University (UNESP), Medical School, Botucatu, Brazil; São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Brazil
| | | | - Joyce Machado Silva
- São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Brazil
| | - Michel Satya Naslavsky
- Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo (USP), São Paulo, SP, Brazil; Human Genome and Stem Cell Research Center, University of São Paulo, São Paulo, SP, Brazil; Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Celso Teixeira Mendes-Junior
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil
| | - Camila Ferreira Bannwart Castro
- São Paulo State University (UNESP), Medical School, Botucatu, Brazil; São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Brazil
| | - Erick C Castelli
- São Paulo State University (UNESP), Medical School, Botucatu, Brazil; São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Brazil.
| |
Collapse
|
9
|
Siemaszko J, Łacina P, Szymczak D, Szeremet A, Majcherek M, Czyż A, Sobczyk-Kruszelnicka M, Fidyk W, Solarska I, Nasiłowska-Adamska B, Skowrońska P, Bieniaszewska M, Tomaszewska A, Basak GW, Giebel S, Wróbel T, Bogunia-Kubik K. Soluble MICA concentrations and genetic variability of MICA and its NKG2D receptor as factors affecting Graft-versus-Host Disease development after allogeneic haematopoietic stem cell transplantation. Hum Immunol 2024; 85:111147. [PMID: 39332041 DOI: 10.1016/j.humimm.2024.111147] [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: 07/09/2024] [Revised: 08/22/2024] [Accepted: 09/17/2024] [Indexed: 09/29/2024]
Abstract
Despite new treatment strategies, graft-versus-host disease (GvHD) remains a formidable complication after allogeneic hematopoietic stem cell transplantation (HSCT). This study aimed to investigate the impact of polymorphisms and expression of MICA and NKG2D receptor on the development of GvHD in allogeneic HSCT recipients. Soluble MICA (sMICA) concentration was measured in serum collected 30 days after transplantation and the genetic variability of MICA and NKG2D genes was evaluated. The frequency of NKG2D+NK cells was determined by flow cytometry before and (21, 30, 60 and 90 days) after transplantation. Recipients with acute GvHD grades II-IV carried the NKG2D rs1049174 C allele more frequently than controls or patients with no or mild disease. Patients with chronic GvHD had higher frequency of NKG2D expressing NK cells posttransplant, reflecting increased activity of their NK cells. Although no direct relationship between MICA SNPs and GvHD were observed, the presence of MICA rs1051792 GG genotype correlated with elevated sMICA levels and increased serum level of sMICA was associated with higher risk of chronic GvHD. Our findings suggest that sMICA concentration may serve as a potential biomarker for chronic GvHD and emphasize the impact of genetic variability of NKG2D and its surface expression on the HSCT outcome.
Collapse
Affiliation(s)
- Jagoda Siemaszko
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Piotr Łacina
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Donata Szymczak
- Department and Clinic of Hematology, Cellular Therapies and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Agnieszka Szeremet
- Department and Clinic of Hematology, Cellular Therapies and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Maciej Majcherek
- Department and Clinic of Hematology, Cellular Therapies and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Anna Czyż
- Department and Clinic of Hematology, Cellular Therapies and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Małgorzata Sobczyk-Kruszelnicka
- Department of Bone Marrow Transplantation and Hematology-Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Wojciech Fidyk
- Department of Bone Marrow Transplantation and Hematology-Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Iwona Solarska
- Institute of Hematology and Blood Transfusion Medicine, Warsaw, Poland
| | | | | | - Maria Bieniaszewska
- Department of Hematology and Transplantology, Medical University of Gdansk, Gdansk, Poland
| | - Agnieszka Tomaszewska
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Grzegorz W Basak
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Sebastian Giebel
- Department of Bone Marrow Transplantation and Hematology-Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Tomasz Wróbel
- Department and Clinic of Hematology, Cellular Therapies and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
| |
Collapse
|
10
|
Huang S, Qin Z, Wang F, Kang Y, Ren B. A potential mechanism of tumor immune escape: Regulation and application of soluble natural killer group 2 member D ligands (Review). Oncol Rep 2024; 52:137. [PMID: 39155864 PMCID: PMC11358674 DOI: 10.3892/or.2024.8796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/31/2024] [Indexed: 08/20/2024] Open
Abstract
The immune system is integral to the surveillance and eradication of tumor cells. Interactions between the natural killer group 2 member D (NKG2D) receptor and its ligands (NKG2DLs) are vital for activating NKG2D receptor‑positive immune cells, such as natural killer cells. This activation enables these cells to identify and destroy tumor cells presenting with NKG2DLs, which is an essential aspect of tumor immunity. However, tumor immune escape is facilitated by soluble NKG2DL (sNKG2DL) shed from the surface of tumor cells. The production of sNKG2DL is predominantly regulated by metalloproteinases [a disintegrin and metalloproteinases (ADAM) and matrix metalloproteinase (MMP) families] and exosomes. sNKG2DL not only diminish immune recognition on the tumor cell surface but also suppress the function of immune cells, such as NK cells, and reduce the expression of the NKG2D receptor. This process promotes immune evasion, progression, and metastasis of tumors. In this review, an in‑depth summary of the mechanisms and factors that influence sNKG2DL production and their contribution to immune suppression within the tumor microenvironment are provided. Furthermore, due to the significant link between sNKG2DLs and tumor progression and metastasis, they have great potential as novel biomarkers. Detectable via liquid biopsies, sNKG2DLs could assess tumor malignancy and prognosis, and act as pivotal targets for immunotherapy. This could lead to the discovery of new drugs or the enhancement of existing treatments. Thus, the application of sNKG2DLs in clinical oncology was explored, offering substantial theoretical support for the development of innovative immunotherapeutic strategies for sNKG2DLs.
Collapse
Affiliation(s)
- Shuhao Huang
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
- Department of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China
| | - Zihao Qin
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
- Department of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China
| | - Feiyang Wang
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
- Department of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yiping Kang
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
- Department of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, P.R. China
| | - Biqiong Ren
- Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China
| |
Collapse
|
11
|
Liu X, Wu F, Pan W, Liu G, Zhang H, Yan D, Zheng S, Ma Z, Ren X. Tumor-associated exosomes in cancer progression and therapeutic targets. MedComm (Beijing) 2024; 5:e709. [PMID: 39247621 PMCID: PMC11380050 DOI: 10.1002/mco2.709] [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: 09/11/2023] [Revised: 08/05/2024] [Accepted: 08/06/2024] [Indexed: 09/10/2024] Open
Abstract
Exosomes are small membrane vesicles that are released by cells into the extracellular environment. Tumor-associated exosomes (TAEs) are extracellular vesicles that play a significant role in cancer progression by mediating intercellular communication and contributing to various hallmarks of cancer. These vesicles carry a cargo of proteins, lipids, nucleic acids, and other biomolecules that can be transferred to recipient cells, modifying their behavior and promoting tumor growth, angiogenesis, immune modulation, and drug resistance. Several potential therapeutic targets within the TAEs cargo have been identified, including oncogenic proteins, miRNAs, tumor-associated antigens, immune checkpoint proteins, drug resistance proteins, and tissue factor. In this review, we will systematically summarize the biogenesis, composition, and function of TAEs in cancer progression and highlight potential therapeutic targets. Considering the complexity of exosome-mediated signaling and the pleiotropic effects of exosome cargoes has challenge in developing effective therapeutic strategies. Further research is needed to fully understand the role of TAEs in cancer and to develop effective therapies that target them. In particular, the development of strategies to block TAEs release, target TAEs cargo, inhibit TAEs uptake, and modulate TAEs content could provide novel approaches to cancer treatment.
Collapse
Affiliation(s)
- Xiaomin Liu
- Lab for Noncoding RNA & Cancer School of Life Sciences Shanghai University Shanghai China
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Fan Wu
- Lab for Noncoding RNA & Cancer School of Life Sciences Shanghai University Shanghai China
| | - Wei Pan
- Lab for Noncoding RNA & Cancer School of Life Sciences Shanghai University Shanghai China
| | - Guangchao Liu
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Hui Zhang
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Dawei Yan
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Saijing Zheng
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Zhongliang Ma
- Lab for Noncoding RNA & Cancer School of Life Sciences Shanghai University Shanghai China
| | - Xiaojun Ren
- Department of Chemistry College of Chemistry and Life Sciences Beijing University of Technology Beijing China
| |
Collapse
|
12
|
Björk E, Israelsson P, Nagaev I, Nagaeva O, Lundin E, Ottander U, Mincheva-Nilsson L. Endometriotic Tissue-derived Exosomes Downregulate NKG2D-mediated Cytotoxicity and Promote Apoptosis: Mechanisms for Survival of Ectopic Endometrial Tissue in Endometriosis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:567-576. [PMID: 38984872 PMCID: PMC11335327 DOI: 10.4049/jimmunol.2300781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 06/17/2024] [Indexed: 07/11/2024]
Abstract
Endometriosis, affecting 10% of women, is defined as implantation, survival, and growth of endometrium-like/endometriotic tissue outside the uterine cavity, causing inflammation, infertility, pain, and susceptibility to ovarian cancer. Despite extensive studies, its etiology and pathogenesis are poorly understood and largely unknown. The prevailing view is that the immune system of endometriosis patients fails to clear ectopically disseminated endometrium from retrograde menstruation. Exosomes are small extracellular vesicles that exhibit immunomodulatory properties. We studied the role of endometriotic tissue-secreted exosomes in the pathophysiology of endometriosis. Two exosome-mediated mechanisms known to impair the immune response were investigated: 1) downregulation of NKG2D-mediated cytotoxicity and 2) FasL- and TRAIL-induced apoptosis of activated immune cells. We showed that secreted endometriotic exosomes isolated from supernatants of short-term explant cultures carry the NKG2D ligands MICA/B and ULBP1-3 and the proapoptotic molecules FasL and TRAIL on their surface, i.e., signature molecules of exosome-mediated immune suppression. Acting as decoys, these exosomes downregulate the NKG2D receptor, impair NKG2D-mediated cytotoxicity, and induce apoptosis of activated PBMCs and Jurkat cells through the FasL- and TRAIL pathway. The secreted endometriotic exosomes create an immunosuppressive gradient at the ectopic site, forming a "protective shield" around the endometriotic lesions. This gradient guards the endometriotic lesions against clearance by a cytotoxic attack and creates immunologic privilege by induction of apoptosis in activated immune cells. Taken together, our results provide a plausible, exosome-based mechanistic explanation for the immune dysfunction and the compromised immune surveillance in endometriosis and contribute novel insights into the pathogenesis of this enigmatic disease.
Collapse
Affiliation(s)
- Emma Björk
- Division of Obstetrics and Gynecology/Örnsköldsvik Hospital, Örnsköldsvik, Sweden
- Department of Clinical Microbiology/Infection and Immunology, Umeå University, Umeå, Sweden
- Department of Clinical Sciences/Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Pernilla Israelsson
- Department of Diagnostics and Intervention/Oncology, Umeå University, Umeå, Sweden
| | - Ivan Nagaev
- Department of Clinical Microbiology/Infection and Immunology, Umeå University, Umeå, Sweden
| | - Olga Nagaeva
- Department of Clinical Microbiology/Infection and Immunology, Umeå University, Umeå, Sweden
| | - Eva Lundin
- Department of Medical Biosciences/Pathology, Umeå University, Umeå, Sweden
| | - Ulrika Ottander
- Department of Clinical Sciences/Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Lucia Mincheva-Nilsson
- Department of Clinical Microbiology/Infection and Immunology, Umeå University, Umeå, Sweden
| |
Collapse
|
13
|
Leifheit ME, Johnson G, Kuzel TM, Schneider JR, Barker E, Yun HD, Ustun C, Goldufsky JW, Gupta K, Marzo AL. Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia. Int J Mol Sci 2024; 25:9448. [PMID: 39273395 PMCID: PMC11394928 DOI: 10.3390/ijms25179448] [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: 06/20/2024] [Revised: 08/21/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
FMS-like tyrosine kinase 3 (FLT3) mutations are genetic changes found in approximately thirty percent of patients with acute myeloid leukemia (AML). FLT3 mutations in AML represent a challenging clinical scenario characterized by a high rate of relapse, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The advent of FLT3 tyrosine kinase inhibitors (TKIs), such as midostaurin and gilteritinib, has shown promise in achieving complete remission. However, a substantial proportion of patients still experience relapse following TKI treatment, necessitating innovative therapeutic strategies. This review critically addresses the current landscape of TKI treatments for FLT3+ AML, with a particular focus on gilteritinib. Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated efficacy in targeting the mutant FLT3 receptor, thereby inhibiting aberrant signaling pathways that drive leukemic proliferation. However, monotherapy with TKIs may not be sufficient to eradicate AML blasts. Specifically, we provide evidence for integrating gilteritinib with mammalian targets of rapamycin (mTOR) inhibitors and interleukin-15 (IL-15) complexes. The combination of gilteritinib, mTOR inhibitors, and IL-15 complexes presents a compelling strategy to enhance the eradication of AML blasts and enhance NK cell killing, offering a potential for improved patient outcomes.
Collapse
Affiliation(s)
- Malia E Leifheit
- Department of Internal Medicine, Division of Hematology, and Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA
| | - Gunnar Johnson
- Department of Internal Medicine, Division of Hematology, and Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA
| | - Timothy M Kuzel
- Department of Internal Medicine, Division of Hematology, and Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA
| | - Jeffrey R Schneider
- Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, IL 60612, USA
| | - Edward Barker
- Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, IL 60612, USA
| | - Hyun D Yun
- Hematology, Oncology, Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA
- Department of Medicine, Division of Hematology, Oncology, School of Medicine, University of California, Irvine, CA 92617, USA
| | - Celalettin Ustun
- Department of Internal Medicine, Division of Hematology, and Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA
| | - Josef W Goldufsky
- Department of Internal Medicine, Division of Hematology, and Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA
| | - Kajal Gupta
- Department of Surgery, Rush University Medical Center, Chicago, IL 60612, USA
| | - Amanda L Marzo
- Department of Internal Medicine, Division of Hematology, and Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA
| |
Collapse
|
14
|
Dong S, Zhao M, Zhu J, Li T, Yan M, Xing K, Liu P, Yu S, Ma J, He H. Natural killer cells: a future star for immunotherapy of head and neck squamous cell carcinoma. Front Immunol 2024; 15:1442673. [PMID: 39234249 PMCID: PMC11371580 DOI: 10.3389/fimmu.2024.1442673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 07/15/2024] [Indexed: 09/06/2024] Open
Abstract
The interplay between immune components and the epithelium plays a crucial role in the development and progression of head and neck squamous cell carcinoma (HNSCC). Natural killer (NK) cells, one of the main tumor-killing immune cell populations, have received increasing attention in HNSCC immunotherapy. In this review, we explore the mechanism underlying the interplay between NK cells and HNSCC. A series of immune evasion strategies utilized by cancer cells restrict HNSCC infiltration of NK cells. Overcoming these limitations can fully exploit the antineoplastic potential of NK cells. We also investigated the tumor-killing efficacy of NK cell-based immunotherapies, immunotherapeutic strategies, and new results from clinical trials. Notably, cetuximab, the most essential component of NK cell-based immunotherapy, inhibits the epidermal growth factor receptor (EGFR) signaling pathway and activates the immune system in conjunction with NK cells, inducing innate effector functions and improving patient prognosis. In addition, we compiled information on other areas for the improvement of patient prognosis using anti-EGFR receptor-based monoclonal antibody drugs and the underlying mechanisms and prognoses of new immunotherapeutic strategies for the treatment of HNSCC.
Collapse
Affiliation(s)
- Shuyan Dong
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ming Zhao
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jin Zhu
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
| | - Ting Li
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Mingze Yan
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Kaixun Xing
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Peng Liu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, China
| | - Shan Yu
- Department of Pathology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jian Ma
- Department of General Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Immunology, Harbin Medical University, Harbin, China
| | - Hongjiang He
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| |
Collapse
|
15
|
Perez Hurtado EC, Henao Agudelo JS, Foganholi da Silva RA, Viração TA, Fernandes CJDC. The role of extracellular vesicles in cancer. CURRENT TOPICS IN MEMBRANES 2024; 94:247-285. [PMID: 39370209 DOI: 10.1016/bs.ctm.2024.06.010] [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: 10/08/2024]
Abstract
Extracellular vesicles (EVs), which include small EVs such as exosomes, play a critical role in intercellular communication and are produced by both cancer and non-cancer cells. Several studies have shown that cancer cells exploit various strategies to regulate the biogenesis, composition, and functions of EVs primarily to promote cancer progression. Given that exosomes originate from major sorting hubs at the limiting membrane of endosomes, they are central to a signaling network that connects external stimuli with intrinsic tumor cell features. Exosomes contain diverse repertoires of molecular cargos, such as proteins, lipids, and nucleic acids, which determine their heterogeneity and functional properties in cancer progression. Therefore, targeting exosome biogenesis will enhance our understanding of tumorigenesis and also promote the discovery of novel approaches for cancer therapy. In this chapter we summarize the machinery of exosome biogenesis and the local, distant, and systemic effects of exosomes released by cancer cells. Furthermore, we explore how these exosomes regulate the anti-tumor immune response and epigenetic mechanisms to sustain cancer progression and their implications in cancer prevention and treatment.
Collapse
Affiliation(s)
| | | | | | - Thiago Albuquerque Viração
- Graduate Program in Environmental and Experimental Pathology, Paulista University, São Paulo, São Paulo, Brazil
| | - Célio Junior da Costa Fernandes
- Department of Biophysics and Pharmacology, Institute of Biosciences, Universidade Estadual Paulista "Júlio de Mesquita Filho" (UNESP), Botucatu, São Paulo, Brazil
| |
Collapse
|
16
|
Tayanloo-Beik A, Eslami A, Sarvari M, Jalaeikhoo H, Rajaeinejad M, Nikandish M, Faridfar A, Rezaei-Tavirani M, Mafi AR, Larijani B, Arjmand B. Extracellular vesicles and cancer stem cells: a deadly duo in tumor progression. Oncol Rev 2024; 18:1411736. [PMID: 39091989 PMCID: PMC11291337 DOI: 10.3389/or.2024.1411736] [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: 04/03/2024] [Accepted: 06/27/2024] [Indexed: 08/04/2024] Open
Abstract
The global incidence of cancer is increasing, with estimates suggesting that there will be 26 million new cases and 17 million deaths per year by 2030. Cancer stem cells (CSCs) and extracellular vesicles (EVs) are key to the resistance and advancement of cancer. They play a crucial role in tumor dynamics and resistance to therapy. CSCs, initially discovered in acute myeloid leukemia, are well-known for their involvement in tumor initiation, progression, and relapse, mostly because of their distinct characteristics, such as resistance to drugs and the ability to self-renew. EVs, which include exosomes, microvesicles, and apoptotic bodies, play a vital role in facilitating communication between cells within the tumor microenvironment (TME). They have a significant impact on cellular behaviors and contribute to genetic and epigenetic changes. This paper analyzes the mutually beneficial association between CSCs and EVs, emphasizing their role in promoting tumor spread and developing resistance mechanisms. This review aims to investigate the interaction between these entities in order to discover new approaches for attacking the complex machinery of cancer cells. It highlights the significance of CSCs and EVs as crucial targets in the advancement of novel cancer treatments, which helps stimulate additional research, promote progress in ideas for cancer treatment, and provide renewed optimism in the effort to reduce the burden of cancer.
Collapse
Affiliation(s)
- Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azin Eslami
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hasan Jalaeikhoo
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | - Mohsen Rajaeinejad
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
- Student Research Committee, Aja University of medical sciences, Tehran, Iran
| | - Mohsen Nikandish
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | - Ali Faridfar
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | | | - Ahmad Rezazadeh Mafi
- Department of Radiation Oncology, Imam Hossein Hospital, Shaheed Beheshti Medical University, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical sciences, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
17
|
Sun Z, Xu Y, Shao B, Dang P, Hu S, Sun H, Chen C, Wang C, Liu J, Liu Y, Hu J. Exosomal circPOLQ promotes macrophage M2 polarization via activating IL-10/STAT3 axis in a colorectal cancer model. J Immunother Cancer 2024; 12:e008491. [PMID: 38782541 PMCID: PMC11116870 DOI: 10.1136/jitc-2023-008491] [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] [Accepted: 05/06/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Accumulating evidence demonstrates that an increased tumor-associated macrophage abundance is often associated with poor prognosis in colorectal cancer (CRC). The mechanism underlying the effect of tumor-derived exosomes on M2 macrophage polarization remains elusive. RESULTS The novel circular RNA circPOLQ exhibited significantly higher expression in CRC tissues than in paired normal tissues. Higher circPOLQ expression was associated with poorer prognosis in patients with CRC. In vitro and in vivo experiments showed that tumor-derived exosomal circPOLQ did not directly regulate CRC cell development but promoted CRC metastatic nodule formation by enhancing M2 macrophage polarization. circPOLQ activated the interleukin-10/signal transducer and activator of transcription 3 axis by targeting miR-379-3 p to promote M2 macrophage polarization. CONCLUSION circPOLQ can enter macrophages via CRC cell-derived exosomes and promote CRC metastatic nodule formation by enhancing M2 macrophage polarization. These findings reveal a tumor-derived exosome-mediated tumor-macrophage interaction potentially affecting CRC metastatic nodule formation.
Collapse
Affiliation(s)
- Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yanxin Xu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bo Shao
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Sciences, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Pengyuan Dang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Shengyun Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Haifeng Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Chen Chen
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Chaoguan Wang
- Department of Radiotherapy, Henan Cancer Hospital Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jinbo Liu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yang Liu
- Department of Radiotherapy, Henan Cancer Hospital Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Junhong Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Sciences, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| |
Collapse
|
18
|
Seller A, Tegeler CM, Mauermann J, Schreiber T, Hagelstein I, Liebel K, Koch A, Heitmann JS, Greiner SM, Hayn C, Dannehl D, Engler T, Hartkopf AD, Hahn M, Brucker SY, Salih HR, Märklin M. Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome. Int J Mol Sci 2024; 25:4126. [PMID: 38612935 PMCID: PMC11012452 DOI: 10.3390/ijms25074126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/02/2024] [Accepted: 04/05/2024] [Indexed: 04/14/2024] Open
Abstract
Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study.
Collapse
Affiliation(s)
- Anna Seller
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Christian M. Tegeler
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
- Department of Peptide-Based Immunotherapy, Institute of Immunology, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
| | - Jonas Mauermann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Tatjana Schreiber
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Ilona Hagelstein
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Kai Liebel
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - André Koch
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Jonas S. Heitmann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
- Department of Peptide-Based Immunotherapy, Institute of Immunology, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
| | - Sarah M. Greiner
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Clara Hayn
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Dominik Dannehl
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Tobias Engler
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Andreas D. Hartkopf
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Markus Hahn
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Sara Y. Brucker
- Department of Women’s Health, University Hospital Tübingen, Calwerstraße 7, 72076 Tübingen, Germany
| | - Helmut R. Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| | - Melanie Märklin
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; (A.S.)
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany
| |
Collapse
|
19
|
Marin MLC, Rached MR, Monteiro SM, Kalil J, Abrao MS, Coelho V. Soluble MICA in endometriosis pathophysiology: Impairs NK cell degranulation and effector functions. Am J Reprod Immunol 2024; 91:e13830. [PMID: 38454570 DOI: 10.1111/aji.13830] [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: 08/10/2023] [Revised: 02/08/2024] [Accepted: 02/09/2024] [Indexed: 03/09/2024] Open
Abstract
PROBLEM Endometriosis exhibits several immune dysfunctions, including deficient natural killer (NK) cell cytotoxicity. MICA (MHC class I chain-related molecule A) is induced by biological stress and soluble MICA (sMICA) negatively modulates the expression of the activating receptor, NKG2D, reducing NK cells activities. We investigated the involvement of soluble MICA in NK cell-deficient activity in endometriosis. METHODS OF STUDY sMICA levels (serum and peritoneal fluid-PF) were evaluated by ELISA. Circulating NK cell subsets quantification and its NKG2D receptor expression, NK cell cytotoxicity and CD107a, IFN-γ and IL-10 expressions by NK cells stimulated with K562 cells were determined by flow cytometry. RESULTS We found higher sMICA levels (serum and PF) in endometriosis, especially in advanced and deep endometriosis. Endometriosis presented lower percentages of CD56dim CD16+ cytotoxic cells and impaired NK cell responses upon stimulation, resulting in lower CD107a and IFN-γ expressions, and deficient NK cell cytotoxicity. NK cell stimulation in the MICA-blocked condition (mimicking the effect of sMICA) showed decreased cytotoxicity in initial endometriosis stages and the emergence of a negative correlation between CD107a expression and sMICA levels. CONCLUSIONS We suggest that soluble MICA is a potential player in endometriosis pathophysiology with involvement in disease progression and severity, contributing to NK cell impaired IFN-γ response and degranulation. NK cell compartment exhibits multiple perturbations, including quantitative deficiency and impaired cytotoxicity, contributing to inadequate elimination of ectopic endometrial tissue.
Collapse
Affiliation(s)
- Maria Lucia Carnevale Marin
- Laboratorio de Imunologia, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
- Laboratorio de Investigaçao Medica 19 (LIM-19), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Marici Rached Rached
- Laboratorio de Imunologia, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Sandra Maria Monteiro
- Laboratorio de Imunologia, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Jorge Kalil
- Laboratorio de Imunologia, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
- Laboratorio de Investigaçao Medica 19 (LIM-19), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
- Instituto de Investigacao em Imunologia, Instituto Nacional de Ciencia e Tecnologia (iii-INCT), Sao Paulo, SP, Brazil
- Divisao de Imunologia Clinica e Alergia, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Mauricio Simoes Abrao
- Divisao de Imunologia Clinica e Alergia, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
- Disciplina de Ginecologia, Departamento de Obstetricia e Ginecologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
- Departamento de Ginecologia, BP - A Beneficencia Portuguesa de Sao Paulo, Sao Paulo, SP, Brazil
| | - Verônica Coelho
- Laboratorio de Imunologia, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
- Instituto de Investigacao em Imunologia, Instituto Nacional de Ciencia e Tecnologia (iii-INCT), Sao Paulo, SP, Brazil
- Divisao de Imunologia Clinica e Alergia, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| |
Collapse
|
20
|
Fernández-Soto D, García-Jiménez ÁF, Casasnovas JM, Valés-Gómez M, Reyburn HT. Elevated levels of cell-free NKG2D-ligands modulate NKG2D surface expression and compromise NK cell function in severe COVID-19 disease. Front Immunol 2024; 15:1273942. [PMID: 38410511 PMCID: PMC10895954 DOI: 10.3389/fimmu.2024.1273942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 01/22/2024] [Indexed: 02/28/2024] Open
Abstract
Introduction It is now clear that coronavirus disease 19 (COVID-19) severity is associated with a dysregulated immune response, but the relative contributions of different immune cells is still not fully understood. SARS CoV-2 infection triggers marked changes in NK cell populations, but there are contradictory reports as to whether these effector lymphocytes play a protective or pathogenic role in immunity to SARS-CoV-2. Methods To address this question we have analysed differences in the phenotype and function of NK cells in SARS-CoV-2 infected individuals who developed either very mild, or life-threatening COVID-19 disease. Results Although NK cells from patients with severe disease appeared more activated and the frequency of adaptive NK cells was increased, they were less potent mediators of ADCC than NK cells from patients with mild disease. Further analysis of peripheral blood NK cells in these patients revealed that a population of NK cells that had lost expression of the activating receptor NKG2D were a feature of patients with severe disease and this correlated with elevated levels of cell free NKG2D ligands, especially ULBP2 and ULBP3 in the plasma of critically ill patients. In vitro, culture in NKG2DL containing patient sera reduced the ADCC function of healthy donor NK cells and this could be blocked by NKG2DL-specific antibodies. Discussion These observations of reduced NK function in severe disease are consistent with the hypothesis that defects in immune surveillance by NK cells permit higher levels of viral replication, rather than that aberrant NK cell function contributes to immune system dysregulation and immunopathogenicity.
Collapse
Affiliation(s)
- Daniel Fernández-Soto
- Department of Immunology and Oncology, National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain
| | - Álvaro F. García-Jiménez
- Department of Immunology and Oncology, National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain
| | - José M. Casasnovas
- Department of Macromolecular Structures, National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain
| | - Mar Valés-Gómez
- Department of Immunology and Oncology, National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain
| | - Hugh T. Reyburn
- Department of Immunology and Oncology, National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain
| |
Collapse
|
21
|
Kim S, Chung H, Kwak JE, Kim YR, Park CH, Kim Y, Cheong JW, Wu J, Shin EC, Cho H, Kim JS. Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma. J Immunother Cancer 2024; 12:e007886. [PMID: 38191242 PMCID: PMC10806558 DOI: 10.1136/jitc-2023-007886] [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] [Accepted: 11/28/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND Major histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released from multiple myeloma (MM) cells during progression, and soluble MIC impairs natural killer group 2D (NKG2D) activating receptor-mediated recognition and function of natural killer (NK) cells. However, whether clearing soluble MIC with a monoclonal antibody (mAb) can restore NK cell activity of MM patients remains undetermined. METHODS We analyzed The Cancer Genome Atlas (TCGA) Multiple Myeloma Research Foundation (MMRF) CoMMpass data set to examine the prognostic significance of MIC expression in MM. We examined the level of soluble MIC in paired peripheral blood (PB) and bone marrow (BM) plasma of patients with MM at diagnosis by ELISA. We evaluated the correlation between the level of soluble MIC and immunophenotype of NK cells from MM patients by multicolor flow cytometry. We also generated MIC-overexpressing MM cell line and characterized the cytotoxic function of patient NK cells in the presence of soluble MIC, and examined the impact of clearing soluble MIC with a humanized mAb (huB10G5). RESULTS We characterize the importance of MICA in MM by revealing the significantly better overall survival of patients with high MICA expression from TCGA MMRF CoMMpass data set. The level of soluble MICA is more highly elevated in MM than in precursor stages, and the concentration of soluble MICA is higher in BM plasma than in PB. The concentration of soluble MICA in BM was correlated with myeloma burden, while it was negatively correlated with the frequency of NKG2D+ NK cells in diagnostic BM aspirates of MM patients. Soluble MICA downregulated NKG2D expression and decreased cytotoxicity of MM patient NK cells ex vivo, which were reversed by a humanized soluble MIC-clearing mAb (huB10G5) with enhanced degranulation of NK cells. CONCLUSIONS Our findings indicate targeting soluble MIC with huB10G5 might be a viable therapeutic approach to promote NKG2D-dependent cellular immunotherapy outcome in MM.
Collapse
Affiliation(s)
- Sojeong Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Haerim Chung
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Jeong-Eun Kwak
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Yu Ri Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Chung Hyun Park
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Yeonhee Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - June-Won Cheong
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Jennifer Wu
- Department of Urology and Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea (the Republic of)
| | - Hyunsoo Cho
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| | - Jin Seok Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
| |
Collapse
|
22
|
Ahmadi M, Abbasi R, Rezaie J. Tumor immune escape: extracellular vesicles roles and therapeutics application. Cell Commun Signal 2024; 22:9. [PMID: 38167133 PMCID: PMC10763406 DOI: 10.1186/s12964-023-01370-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/28/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Immune escape, a process by which tumor cells evade immune surveillance, remains a challenge for cancer therapy. Tumor cells produce extracellular vesicles (EVs) that participate in immune escape by transferring bioactive molecules between cells. EVs refer to heterogeneous vesicles that participate in intercellular communication. EVs from tumor cells usually carry tumor antigens and have been considered a source of tumor antigens to induce anti-tumor immunity. However, evidence also suggests that these EVs can accelerate immune escape by carrying heat shock proteins (HSPs), programmed death-ligand 1 (PD-L1), etc. to immune cells, suppressing function and exhausting the immune cells pool. EVs are progressively being evaluated for therapeutic implementation in cancer therapies. EVs-based immunotherapies involve inhibiting EVs generation, using natural EVs, and harnessing engineering EVs. All approaches are associated with advantages and disadvantages. The EVs heterogeneity and diverse physicochemical properties are the main challenges to their clinical applications. SHORT CONCLUSION Although EVs are criminal; they can be useful for overcoming immune escape. This review discusses the latest knowledge on EVs population and sheds light on the function of tumor-derived EVs in immune escape. It also describes EVs-based immunotherapies with a focus on engineered EVs, followed by challenges that hinder the clinical translation of EVs that are essential to be addressed in future investigations. Video Abstract.
Collapse
Affiliation(s)
- Mahdi Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Abbasi
- Department of Biology, Urmia University, Urmia, Iran
| | - Jafar Rezaie
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran.
| |
Collapse
|
23
|
Schinstock CA, Agrawal A, Valenzuela NM. The Significance of Major Histocompatibility Complex Class I Chain-related Molecule A in Solid Organ and Hematopoietic Stem Cell Transplantation: A Comprehensive Overview. Transplantation 2024; 108:115-126. [PMID: 37218026 DOI: 10.1097/tp.0000000000004643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Improving long-term allograft survival and minimizing recipient morbidity is of key importance in all of transplantation. Improved matching of classical HLA molecules and avoiding HLA donor-specific antibody has been a major focus; however, emerging data suggest the relevance of nonclassical HLA molecules, major histocompatibility complex class I chain-related gene A (MICA) and B, in transplant outcomes. The purpose of this review is to discuss the structure, function, polymorphisms, and genetics of the MICA molecule and relates this to clinical outcomes in solid organ and hematopoietic stem cell transplantation. The tools available for genotyping and antibody detection will be reviewed combined with a discussion of their shortcomings. Although data supporting the relevance of MICA molecules have accumulated, key knowledge gaps exist and should be addressed before widespread implementation of MICA testing for recipients pre- or posttransplantation.
Collapse
Affiliation(s)
- Carrie A Schinstock
- Von Liebig Center for Transplant and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - Amogh Agrawal
- Von Liebig Center for Transplant and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - Nicole M Valenzuela
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, Los Angeles, CA
| |
Collapse
|
24
|
Keyvani V, Ghale-Noie ZN, Mollazadeh S, Mahmoudian RA, Ghorbani E, Naderi H, Khazaei M, Hassanian SM, Ferns GA, Avan A, Anvari K. Recent Progress in the Application of Exosome Analysis in Ovarian Cancer Management. Curr Cancer Drug Targets 2024; 24:920-929. [PMID: 38284712 DOI: 10.2174/0115680096281906231213055422] [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: 09/12/2023] [Revised: 10/22/2023] [Accepted: 10/25/2023] [Indexed: 01/30/2024]
Abstract
Exosomes are very small (nano-sized) vesicles participating in tumor development by involvement in intercellular communication mediated by transferring biocomponents. Exosomes appear to play vital roles in various cancer development, such as ovarian cancer, a common malignancy in women. Several hallmarks of ovarian cancer are reported to be affected by the exosomemediated cellular cross-talk, including modulating peritoneal dissemination and chemoresistance. Since the expression of some biomolecules, such as miRNAs and mRNA, is changed in ovarian cancer, these exo-biomolecules can be applied as prognostic, diagnostic, and therapeutic biomarkers. Also, the selective loading of specific chemotherapeutic agents into exosomes highlights these biocarries as potential delivery devices. Exosomes could be artificially provided and engineered to better target the site of interest in ovarian cancer. In the present review, we summarize the notable achievement of exosome application in ovarian cancer management to gain applicable transitional insight against this cancer.
Collapse
Affiliation(s)
- Vahideh Keyvani
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zari Naderi Ghale-Noie
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Mollazadeh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Reihaneh Alsadat Mahmoudian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elnaz Ghorbani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- College of Medicine, University of Warith Al-Anbiyaa, Karbala, Iraq
| | - Hamid Naderi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, BN1 9PH, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, 4059, Australia
- College of Medicine and Health Sciences, National University of Science and Technology, Sultanate of Oman
| | - Kazem Anvari
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
25
|
Su F, Zhang Y, Maimaiti S, Chen S, Shen Y, Feng M, Guo Z, Tan L, He J. Mechanisms and characteristics of subcapsular sinus macrophages in tumor immunity: a narrative review. Transl Cancer Res 2023; 12:3779-3791. [PMID: 38192994 PMCID: PMC10774050 DOI: 10.21037/tcr-23-2032] [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: 11/02/2023] [Accepted: 11/27/2023] [Indexed: 01/10/2024]
Abstract
Background and Objective Lymph nodes constitute an integral component of the secondary lymphoid organs, housing a diverse population of macrophages. Macrophages exhibit heterogeneity in terms of localization, phenotype and ontogeny. Recent evidence has established that subcapsular sinus macrophages (SCSMs) are the initial cells exposed to antigens from afferent lymph vessels, playing a crucial role in the host immune response against invading pathogens and tumor cells. In order to summarize the role and mechanisms of SCSM in tumor immunity, this study systematically reviews research on SCSMs in tumor immunity. Methods A systematic search was conducted in PubMed and Web of Science to identify articles investigating clinical significance and mechanisms of SCSMs. Study eligibility was independently evaluated by two authors based on the assessment of titles, abstracts and full-texts. Key Content and Findings The narrative review included a total of 17 studies. Previous research consistently showed that a high level of SCSM in patients with various carcinomas is associated with a favorable long-term prognosis. SCSM acts as the front-line defender in antitumor activity, engaging in intricate communication with other immune cells. Moreover, SCSM could directly and indirectly modulate tumor immunity, and the integrity of SCSM layer is interrupted in disease status. Several studies explored the feasibility of targeting SCSM to activate immunity against tumors. However, the direct molecular interactions and alternation in signal pathway in the tumor immunity of SCSM are less well established in previous researches. Conclusions This narrative review underscores the critical role of SCSM in tumor immunity. Future studies should focus on the deeper mechanism underlying SCSMs and explore their clinical applications.
Collapse
Affiliation(s)
- Feng Su
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yutao Zhang
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science & Technology, Shanghai, China
| | | | - Shanglin Chen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yaxing Shen
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mingxiang Feng
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiqiang Guo
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science & Technology, Shanghai, China
| | - Lijie Tan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
26
|
Asleh K, Dery V, Taylor C, Davey M, Djeungoue-Petga MA, Ouellette RJ. Extracellular vesicle-based liquid biopsy biomarkers and their application in precision immuno-oncology. Biomark Res 2023; 11:99. [PMID: 37978566 PMCID: PMC10655470 DOI: 10.1186/s40364-023-00540-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 11/06/2023] [Indexed: 11/19/2023] Open
Abstract
While the field of precision oncology is rapidly expanding and more targeted options are revolutionizing cancer treatment paradigms, therapeutic resistance particularly to immunotherapy remains a pressing challenge. This can be largely attributed to the dynamic tumor-stroma interactions that continuously alter the microenvironment. While to date most advancements have been made through examining the clinical utility of tissue-based biomarkers, their invasive nature and lack of a holistic representation of the evolving disease in a real-time manner could result in suboptimal treatment decisions. Thus, using minimally-invasive approaches to identify biomarkers that predict and monitor treatment response as well as alert to the emergence of recurrences is of a critical need. Currently, research efforts are shifting towards developing liquid biopsy-based biomarkers obtained from patients over the course of disease. Liquid biopsy represents a unique opportunity to monitor intercellular communication within the tumor microenvironment which could occur through the exchange of extracellular vesicles (EVs). EVs are lipid bilayer membrane nanoscale vesicles which transfer a plethora of biomolecules that mediate intercellular crosstalk, shape the tumor microenvironment, and modify drug response. The capture of EVs using innovative approaches, such as microfluidics, magnetic beads, and aptamers, allow their analysis via high throughput multi-omics techniques and facilitate their use for biomarker discovery. Artificial intelligence, using machine and deep learning algorithms, is advancing multi-omics analyses to uncover candidate biomarkers and predictive signatures that are key for translation into clinical trials. With the increasing recognition of the role of EVs in mediating immune evasion and as a valuable biomarker source, these real-time snapshots of cellular communication are promising to become an important tool in the field of precision oncology and spur the recognition of strategies to block resistance to immunotherapy. In this review, we discuss the emerging role of EVs in biomarker research describing current advances in their isolation and analysis techniques as well as their function as mediators in the tumor microenvironment. We also highlight recent lung cancer and melanoma studies that point towards their application as predictive biomarkers for immunotherapy and their potential clinical use in precision immuno-oncology.
Collapse
Affiliation(s)
- Karama Asleh
- Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada.
| | - Valerie Dery
- Department of Chemistry and Biochemistry, Université de Moncton, Moncton, New Brunswick, Canada
| | - Catherine Taylor
- Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada
| | - Michelle Davey
- Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada
| | | | - Rodney J Ouellette
- Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada
- Department of Chemistry and Biochemistry, Université de Moncton, Moncton, New Brunswick, Canada
- Dr Georges L. Dumont University Hospital, Vitalite Health Network, Moncton, New Brunswick, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
| |
Collapse
|
27
|
Klussmeier A, Putke K, Klasberg S, Kohler M, Sauter J, Schefzyk D, Schöfl G, Massalski C, Schäfer G, Schmidt AH, Roers A, Lange V. High population frequencies of MICA copy number variations originate from independent recombination events. Front Immunol 2023; 14:1297589. [PMID: 38035108 PMCID: PMC10684724 DOI: 10.3389/fimmu.2023.1297589] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 10/24/2023] [Indexed: 12/02/2023] Open
Abstract
MICA is a stress-induced ligand of the NKG2D receptor that stimulates NK and T cell responses and was identified as a key determinant of anti-tumor immunity. The MICA gene is located inside the MHC complex and is in strong linkage disequilibrium with HLA-B. While an HLA-B*48-linked MICA deletion-haplotype was previously described in Asian populations, little is known about other MICA copy number variations. Here, we report the genotyping of more than two million individuals revealing high frequencies of MICA duplications (1%) and MICA deletions (0.4%). Their prevalence differs between ethnic groups and can rise to 2.8% (Croatia) and 9.2% (Mexico), respectively. Targeted sequencing of more than 70 samples indicates that these copy number variations originate from independent nonallelic homologous recombination events between segmental duplications upstream of MICA and MICB. Overall, our data warrant further investigation of disease associations and consideration of MICA copy number data in oncological study protocols.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Axel Roers
- Institute for Immunology, Medical Faculty Carl Gustav Carus, University of Technology (TU) Dresden, Dresden, Germany
- Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | | |
Collapse
|
28
|
Lopez-Montaño M, Jimenez-Ortega L, Cruz-Hernandez TR, Hernandez-Chavez VG, Montiel-Cervantes LA, Reyes-Maldonado E, Vela-Ojeda J. Significant increase in MIC-A and MIC-B and soluble MIC-A and MIC-B in canine lymphomas. Vet Immunol Immunopathol 2023; 264:110647. [PMID: 37672843 DOI: 10.1016/j.vetimm.2023.110647] [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: 06/14/2023] [Revised: 08/10/2023] [Accepted: 08/23/2023] [Indexed: 09/08/2023]
Abstract
Non-Hodkin's lymphoma (NHL) is the most frequent hematologic malignancy in humans and dogs. NKG2D is one of the most critical receptors on NK cells, recognizing their natural ligands on malignant cells such as A and B major histocompatibility complex-related proteins (MIC-A and MIC-B). Soluble molecules (sMIC-A and sMIC-B) can interfere with immune synapsis between NK cells and tumor cells, impeding NK cytotoxicity. The main objectives of this study were to analyze, in dogs with diffuse large B cell lymphoma, NK cell lymphoma, and reactive lymphadenopathies, the role of NK cells, their activating receptors NKG2D and NKp46, and their ligands MIC-A and MIC-B, as well as soluble molecules sMIC-A and sMIC-B. Thirty-six dogs with a possible diagnosis of NHL and eight healthy dogs were studied. NHL was diagnosed in 28 (78 %) dogs; in the other 8 (22 %), reactive lymphadenopathies were present. Most of the lymphomas corresponded to B cell NHL (82 %). The most predominant subtype was diffuse large B cell lymphoma (21, 71.5 %), followed by five cases (18 %) that were Non-B Non-T lymphomas (presumably NK cell lymphomas) and other B cell lymphomas (3, 10.5%). There were no cases of T cell NHL. MIC-A was positive in 7 of 27 (26 %) cases of NHL, and MIC-B in 20 of 27 (74 %) NHL. In non-malignant lymphadenopathies, three (37.5 %) dogs were positive for MIC-A, and five (62.5 %) expressed MIC-B. Dogs with lymphoma had higher numbers of NK cells than eight healthy dogs. In 15 dogs (12 cases with NHL and three cases with reactive adenopathies) and eight controls, there were no differences in the number of NK cells expressing NKP46 and NKG2D. NHL dogs had higher values of sMIC-A and sMIC-B. B-cell and NK cell lymphomas correspond to 86 % and 14 % of all canine lymphomas. MIC-A, MIC-B, and sMIC-A and sMIC-B were increased in canine lymphomas.
Collapse
Affiliation(s)
- Maresa Lopez-Montaño
- Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Manuel Carpio y Plan de Ayala, Del. Miguel Hidalgo, 11340 Mexico City, Mexico
| | - Laura Jimenez-Ortega
- Escuela Superior de Medicina, Sección de Estudios de Posgrado e Investigación, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón S/N, Col. Casco de Santo Tomás, CP 11340 Mexico City, Mexico
| | - Teresa Rocio Cruz-Hernandez
- Centro de diagnóstico veterinario especializado (cedivete), Área de histopatología Calle Iztapalapa 9, San Antonio, Iztapalapa, CP 09900 Mexico City, Mexico
| | - Victor Gabriel Hernandez-Chavez
- Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Manuel Carpio y Plan de Ayala, Del. Miguel Hidalgo, 11340 Mexico City, Mexico
| | - Laura Arcelia Montiel-Cervantes
- Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Manuel Carpio y Plan de Ayala, Del. Miguel Hidalgo, 11340 Mexico City, Mexico; Departamento de Hematología, Unidad Médica de Alta Especialidad, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Seris y Zaachila S/N Colonia La Raza, Azcapotzalco, 02990 Mexico City, Mexico
| | - Elba Reyes-Maldonado
- Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Manuel Carpio y Plan de Ayala, Del. Miguel Hidalgo, 11340 Mexico City, Mexico
| | - Jorge Vela-Ojeda
- Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Manuel Carpio y Plan de Ayala, Del. Miguel Hidalgo, 11340 Mexico City, Mexico.
| |
Collapse
|
29
|
Singh S, Barik D, Arukha AP, Prasad S, Mohapatra I, Singh A, Singh G. Small Molecule Targeting Immune Cells: A Novel Approach for Cancer Treatment. Biomedicines 2023; 11:2621. [PMID: 37892995 PMCID: PMC10604364 DOI: 10.3390/biomedicines11102621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/05/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Conventional and cancer immunotherapies encompass diverse strategies to address various cancer types and stages. However, combining these approaches often encounters limitations such as non-specific targeting, resistance development, and high toxicity, leading to suboptimal outcomes in many cancers. The tumor microenvironment (TME) is orchestrated by intricate interactions between immune and non-immune cells dictating tumor progression. An innovative avenue in cancer therapy involves leveraging small molecules to influence a spectrum of resistant cell populations within the TME. Recent discoveries have unveiled a phenotypically diverse cohort of innate-like T (ILT) cells and tumor hybrid cells (HCs) exhibiting novel characteristics, including augmented proliferation, migration, resistance to exhaustion, evasion of immunosurveillance, reduced apoptosis, drug resistance, and heightened metastasis frequency. Leveraging small-molecule immunomodulators to target these immune players presents an exciting frontier in developing novel tumor immunotherapies. Moreover, combining small molecule modulators with immunotherapy can synergistically enhance the inhibitory impact on tumor progression by empowering the immune system to meticulously fine-tune responses within the TME, bolstering its capacity to recognize and eliminate cancer cells. This review outlines strategies involving small molecules that modify immune cells within the TME, potentially revolutionizing therapeutic interventions and enhancing the anti-tumor response.
Collapse
Affiliation(s)
- Shilpi Singh
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Debashis Barik
- Center for Computational Natural Science and Bioinformatics, International Institute of Information Technology, Hyderabad 500032, Telangana, India
| | | | | | - Iteeshree Mohapatra
- Department of Veterinary and Biomedical Sciences, University of Minnesota—Twin Cities, Saint Paul, MN 55108, USA
| | - Amar Singh
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Gatikrushna Singh
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA
| |
Collapse
|
30
|
Kol I, Rishiq A, Cohen M, Kahlon S, Pick O, Dassa L, Stein N, Bar-On Y, Wolf DG, Seidel E, Mandelboim O. CLPTM1L is a GPI-anchoring pathway component targeted by HCMV. J Cell Biol 2023; 222:e202207104. [PMID: 37389656 PMCID: PMC10316631 DOI: 10.1083/jcb.202207104] [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] [Received: 07/21/2022] [Revised: 04/03/2023] [Accepted: 05/19/2023] [Indexed: 07/01/2023] Open
Abstract
The GPI-anchoring pathway plays important roles in normal development and immune modulation. MHC Class I Polypeptide-related Sequence A (MICA) is a stress-induced ligand, downregulated by human cytomegalovirus (HCMV) to escape immune recognition. Its most prevalent allele, MICA*008, is GPI-anchored via an uncharacterized pathway. Here, we identify cleft lip and palate transmembrane protein 1-like protein (CLPTM1L) as a GPI-anchoring pathway component and show that during infection, the HCMV protein US9 downregulates MICA*008 via CLPTM1L. We show that the expression of some GPI-anchored proteins (CD109, CD59, and MELTF)-but not others (ULBP2, ULBP3)-is CLPTM1L-dependent, and further show that like MICA*008, MELTF is downregulated by US9 via CLPTM1L during infection. Mechanistically, we suggest that CLPTM1L's function depends on its interaction with a free form of PIG-T, normally a part of the GPI transamidase complex. We suggest that US9 inhibits this interaction and thereby downregulates the expression of CLPTM1L-dependent proteins. Altogether, we report on a new GPI-anchoring pathway component that is targeted by HCMV.
Collapse
Affiliation(s)
- Inbal Kol
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Ahmed Rishiq
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Mevaseret Cohen
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Shira Kahlon
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Ophir Pick
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Liat Dassa
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Natan Stein
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Yotam Bar-On
- Department of Immunology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Dana G. Wolf
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
- Clinical Virology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Einat Seidel
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| | - Ofer Mandelboim
- The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
| |
Collapse
|
31
|
Hu M, Kenific CM, Boudreau N, Lyden D. Tumor-derived nanoseeds condition the soil for metastatic organotropism. Semin Cancer Biol 2023; 93:70-82. [PMID: 37178822 PMCID: PMC10362948 DOI: 10.1016/j.semcancer.2023.05.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 05/15/2023]
Abstract
Primary tumors secrete a variety of factors to turn distant microenvironments into favorable and fertile 'soil' for subsequent metastases. Among these 'seeding' factors that initiate pre-metastatic niche (PMN) formation, tumor-derived extracellular vesicles (EVs) are of particular interest as tumor EVs can direct organotropism depending on their surface integrin profiles. In addition, EVs also contain versatile, bioactive cargo, which include proteins, metabolites, lipids, RNA, and DNA fragments. The cargo incorporated into EVs is collectively shed from cancer cells and cancer-associated stromal cells. Increased understanding of how tumor EVs promote PMN establishment and detection of EVs in bodily fluids highlight how tumor EVs could serve as potential diagnostic and prognostic biomarkers, as well as provide a therapeutic target for metastasis prevention. This review focuses on tumor-derived EVs and how they direct organotropism and subsequently modulate stromal and immune microenvironments at distal sites to facilitate PMN formation. We also outline the progress made thus far towards clinical applications of tumor EVs.
Collapse
Affiliation(s)
- Mengying Hu
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Candia M Kenific
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Nancy Boudreau
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
| | - David Lyden
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
| |
Collapse
|
32
|
Dixson AC, Dawson TR, Di Vizio D, Weaver AM. Context-specific regulation of extracellular vesicle biogenesis and cargo selection. Nat Rev Mol Cell Biol 2023; 24:454-476. [PMID: 36765164 PMCID: PMC10330318 DOI: 10.1038/s41580-023-00576-0] [Citation(s) in RCA: 241] [Impact Index Per Article: 120.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2023] [Indexed: 02/12/2023]
Abstract
To coordinate, adapt and respond to biological signals, cells convey specific messages to other cells. An important aspect of cell-cell communication involves secretion of molecules into the extracellular space. How these molecules are selected for secretion has been a fundamental question in the membrane trafficking field for decades. Recently, extracellular vesicles (EVs) have been recognized as key players in intercellular communication, carrying not only membrane proteins and lipids but also RNAs, cytosolic proteins and other signalling molecules to recipient cells. To communicate the right message, it is essential to sort cargoes into EVs in a regulated and context-specific manner. In recent years, a wealth of lipidomic, proteomic and RNA sequencing studies have revealed that EV cargo composition differs depending upon the donor cell type, metabolic cues and disease states. Analyses of distinct cargo 'fingerprints' have uncovered mechanistic linkages between the activation of specific molecular pathways and cargo sorting. In addition, cell biology studies are beginning to reveal novel biogenesis mechanisms regulated by cellular context. Here, we review context-specific mechanisms of EV biogenesis and cargo sorting, focusing on how cell signalling and cell state influence which cellular components are ultimately targeted to EVs.
Collapse
Affiliation(s)
- Andrew C Dixson
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - T Renee Dawson
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Center for Extracellular Vesicle Research, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Dolores Di Vizio
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Alissa M Weaver
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Center for Extracellular Vesicle Research, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
| |
Collapse
|
33
|
Tsunedomi R, Shindo Y, Nakajima M, Yoshimura K, Nagano H. The tumor immune microenvironment in pancreatic cancer and its potential in the identification of immunotherapy biomarkers. Expert Rev Mol Diagn 2023; 23:1121-1134. [PMID: 37947389 DOI: 10.1080/14737159.2023.2281482] [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: 02/21/2023] [Accepted: 11/06/2023] [Indexed: 11/12/2023]
Abstract
INTRODUCTION Pancreatic cancer (PC) has an extremely poor prognosis, even with surgical resection and triplet chemotherapy treatment. Cancer immunotherapy has been recently approved for tumor-agnostic treatment with genome analysis, including in PC. However, it has limited efficacy. AREAS COVERED In addition to the low tumor mutation burden, one of the difficulties of immunotherapy in PC is the presence of abundant stromal cells in its microenvironment. Among stromal cells, cancer-associated fibroblasts (CAFs) play a major role in immunotherapy resistance, and CAF-targeted therapies are currently under development, including those in combination with immunotherapies. Meanwhile, microbiomes and tumor-derived exosomes (TDEs) have been shown to alter the behavior of distant receptor cells in PC. This review discusses the role of CAFs, microbiomes, and TDEs in PC tumor immunity. EXPERT OPINION Elucidating the mechanisms by which CAFs, microbiomes, and TDEs are involved in the tumorigenesis of PC will be helpful for developing novel immunotherapeutic strategies and identifying companion biomarkers for immunotherapy. Spatial single-cell analysis of the tumor microenvironment will be useful for identifying biomarkers of PC immunity. Furthermore, given the complexity of immune mechanisms, artificial intelligence models will be beneficial for predicting the efficacy of immunotherapy.
Collapse
Affiliation(s)
- Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Yoshitaro Shindo
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Masao Nakajima
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Kiyoshi Yoshimura
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan
- Department of Clinical Immuno-Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Setagaya, Tokyo, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| |
Collapse
|
34
|
Petersdorf EW, McKallor C, Malkki M, He M, Spellman SR, Hsu KC, Strong RK, Gooley T, Stevenson P. Role of NKG2D ligands and receptor in haploidentical related donor hematopoietic cell transplantation. Blood Adv 2023; 7:2888-2896. [PMID: 36763517 PMCID: PMC10300293 DOI: 10.1182/bloodadvances.2022008922] [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] [Received: 09/12/2022] [Revised: 11/10/2022] [Accepted: 12/06/2022] [Indexed: 02/11/2023] Open
Abstract
The recurrence of malignancy after hematopoietic cell transplantation (HCT) is the primary cause of transplantation failure. The NKG2D axis is a powerful pathway for antitumor responses, but its role in the control of malignancy after HCT is not well-defined. We tested the hypothesis that gene variation of the NKG2D receptor and its ligands MICA and MICB affect relapse and survival in 1629 patients who received a haploidentical HCT for the treatment of a malignant blood disorder. Patients and donors were characterized for MICA residue 129, the exon 5 short tandem repeat (STR), and MICB residues 52, 57, 98, and 189. Donors were additionally defined for the presence of NKG2D residue 72. Mortality was higher in patients with MICB-52Asn relative to those with 52Asp (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.24-2.71; P = .002) and lower in those with MICA-STR mismatch than in those with STR match (HR, 0.66; 95% CI, 0.54-0.79; P = .00002). Relapse was lower with NKG2D-72Thr donors than with 72Ala donors (relapse HR, 0.57; 95% CI, 0.35-0.91; P = .02). The protective effects of patient MICB-52Asp with donor MICA-STR mismatch and NKG2D-72Thr were enhanced when all 3 features were present. The NKG2D ligand/receptor pathway is a transplantation determinant. The immunobiology of relapse is defined by the concerted effects of MICA, MICB, and NKG2D germ line variation. Consideration of NKG2D ligand/receptor pairings may improve survival for future patients.
Collapse
Affiliation(s)
- Effie W. Petersdorf
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
| | - Caroline McKallor
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA
| | - Mari Malkki
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA
| | - Meilun He
- National Marrow Donor Program/BeTheMatch, Center for International Blood and Marrow Transplant Research, Minneapolis, MN
| | - Stephen R. Spellman
- National Marrow Donor Program/BeTheMatch, Center for International Blood and Marrow Transplant Research, Minneapolis, MN
| | - Katharine C. Hsu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Roland K. Strong
- Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA
| | - Ted Gooley
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA
| | - Phil Stevenson
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA
| |
Collapse
|
35
|
Greening DW, Xu R, Ale A, Hagemeyer CE, Chen W. Extracellular vesicles as next generation immunotherapeutics. Semin Cancer Biol 2023; 90:73-100. [PMID: 36773820 DOI: 10.1016/j.semcancer.2023.02.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/01/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023]
Abstract
Extracellular vesicles (EVs) function as a mode of intercellular communication and molecular transfer to elicit diverse biological/functional response. Accumulating evidence has highlighted that EVs from immune, tumour, stromal cells and even bacteria and parasites mediate the communication of various immune cell types to dynamically regulate host immune response. EVs have an innate capacity to evade recognition, transport and transfer functional components to target cells, with subsequent removal by the immune system, where the immunological activities of EVs impact immunoregulation including modulation of antigen presentation and cross-dressing, immune activation, immune suppression, and immune surveillance, impacting the tumour immune microenvironment. In this review, we outline the recent progress of EVs in immunorecognition and therapeutic intervention in cancer, including vaccine and targeted drug delivery and summarise their utility towards clinical translation. We highlight the strategies where EVs (natural and engineered) are being employed as a therapeutic approach for immunogenicity, tumoricidal function, and vaccine development, termed immuno-EVs. With seminal studies providing significant progress in the sequential development of engineered EVs as therapeutic anti-tumour platforms, we now require direct assessment to tune and improve the efficacy of resulting immune responses - essential in their translation into the clinic. We believe such a review could strengthen our understanding of the progress in EV immunobiology and facilitate advances in engineering EVs for the development of novel EV-based immunotherapeutics as a platform for cancer treatment.
Collapse
Affiliation(s)
- David W Greening
- Molecular Proteomics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, Australia; Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Victoria, Australia; Central Clinical School, Monash University, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Victoria, Australia.
| | - Rong Xu
- Central Clinical School, Monash University, Victoria, Australia; Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Anukreity Ale
- Central Clinical School, Monash University, Victoria, Australia; Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Christoph E Hagemeyer
- Central Clinical School, Monash University, Victoria, Australia; Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Weisan Chen
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Victoria, Australia
| |
Collapse
|
36
|
Gonzalez-Melero L, Hernandez RM, Santos-Vizcaino E, Igartua M. Tumour-derived extracellular vesicle based vaccines for melanoma treatment. Drug Deliv Transl Res 2023; 13:1520-1542. [PMID: 37022605 PMCID: PMC10102154 DOI: 10.1007/s13346-023-01328-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2023] [Indexed: 04/07/2023]
Abstract
The interest of extracellular vesicles (EVs) in cancer immunotherapy is increasing every day. EVs are lipid bilayer vesicles released by most cells, which contain the molecular signature of their parent cell. Melanoma-derived EVs present antigens specific to this aggressive type of cancer, but they also exert immunomodulatory and pro-metastatic activity. Until now, most reviews focus on the immunoevasive characteristics of tumour-derived EVs, but do not help to overcome the issues related to them. In this review, we describe isolation methods of EVs from melanoma patients and most interesting markers to oversee their effect if they are used as antigen carriers. We also discuss the methods developed so far to overcome the lack of immunogenicity of melanoma-derived EVs, which includes EV modification or adjuvant co-administration. In summary, we conclude that EVs can be an interesting antigen source for immunotherapy development once EV obtaining is optimised and the understanding of the mechanisms behind their multiple effects is further understood.
Collapse
Affiliation(s)
- Lorena Gonzalez-Melero
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
- Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Rosa Maria Hernandez
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid, Spain
- Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Edorta Santos-Vizcaino
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid, Spain.
- Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain.
| | - Manoli Igartua
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, Madrid, Spain.
- Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain.
| |
Collapse
|
37
|
Morimoto Y, Yamashita N, Daimon T, Hirose H, Yamano S, Haratake N, Ishikawa S, Bhattacharya A, Fushimi A, Ahmad R, Takahashi H, Dashevsky O, Mitsiades C, Kufe D. MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells. J Immunother Cancer 2023; 11:e006238. [PMID: 36754452 PMCID: PMC9923360 DOI: 10.1136/jitc-2022-006238] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND The MUC1-C protein evolved in mammals to protect barrier tissues from loss of homeostasis; however, MUC1-C promotes oncogenesis in association with chronic inflammation. Aberrant expression of MUC1-C in cancers has been linked to depletion and dysfunction of T cells in the tumor microenvironment. In contrast, there is no known involvement of MUC1-C in the regulation of natural killer (NK) cell function. METHODS Targeting MUC1-C genetically and pharmacologically in cancer cells was performed to assess effects on intracellular and cell surface expression of the MHC class I chain-related polypeptide A (MICA) and MICB ligands. The MICA/B promoters were analyzed for H3K27 and DNA methylation. Shedding of MICA/B was determined by ELISA. MUC1-C interactions with ERp5 and RAB27A were assessed by coimmunoprecipitation and direct binding studies. Exosomes were isolated for analysis of secretion. Purified NK cells were assayed for killing of cancer cell targets. RESULTS Our studies demonstrate that MUC1-C represses expression of the MICA and MICB ligands that activate the NK group 2D receptor. We show that the inflammatory MUC1-C→NF-κB pathway drives enhancer of zeste homolog 2-mediated and DNMT-mediated methylation of the MICA and MICB promoter regions. Targeting MUC1-C genetically and pharmacologically with the GO-203 inhibitor induced intracellular and cell surface MICA/B expression but not MICA/B cleavage. Mechanistically, MUC1-C regulates the ERp5 thiol oxidoreductase that is necessary for MICA/B protease digestion and shedding. In addition, MUC1-C interacts with the RAB27A protein, which is required for exosome formation and secretion. As a result, targeting MUC1-C markedly inhibited secretion of exosomes expressing MICA/B. In concert with these results, we show that targeting MUC1-C promotes NK cell-mediated killing. CONCLUSIONS These findings uncover pleotropic mechanisms by which MUC1-C confers evasion of cancer cells to NK cell recognition and destruction.
Collapse
Affiliation(s)
- Yoshihiro Morimoto
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Nami Yamashita
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Tatsuaki Daimon
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Haruka Hirose
- Division of Systems Biology, Nagoya University Graduate School of Medicine Faculty of Medicine, Nagoya, Japan
| | - Shizuka Yamano
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Broad Institute, Cambridge, Massachusetts, USA
| | - Naoki Haratake
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Satoshi Ishikawa
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Atrayee Bhattacharya
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Atsushi Fushimi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Rehan Ahmad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Osaka University, Suita, Japan
| | - Olga Dashevsky
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Broad Institute, Cambridge, Massachusetts, USA
| | - Constantine Mitsiades
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Broad Institute, Cambridge, Massachusetts, USA
| | - Donald Kufe
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| |
Collapse
|
38
|
Abstract
INTRODUCTION New methods in cancer immunotherapy, such as chimeric antigen receptor (CAR)-T cells, have shown promising results in destroying malignant cells. However, limitations and side effects of CAR-T cell therapy, such as graft-versus-host disease (GVHD), neurotoxicity, and cytokine release syndrome, have motivated researchers to investigate safer alternative cells like natural killer (NK) cells. AREA COVERED NK cells can effectively recognize hematologic malignant cells and destroy them. Many clinical and preclinical studies investigate the efficacy of CAR-NK cells in treating lymphoma and other hematologic malignancies. The results of published clinical trials and preclinical studies have shown that CAR-NK cells could be an appropriate choice for treating lymphoma. In this review, we discuss the characteristics of CAR-NK cells, their role in treating B-cell and T-cell lymphoma, and the challenges faced by using them. We also highlight clinical trials using CAR-NK cells for treating lymphoma. EXPERT OPINION CAR-NK cells have shown promising results in cancer therapy, especially B-cell lymphoma, with a much lower risk for GVHD, cytokine release syndrome, and neurotoxicity than CAR-T cells. Further investigations are required to overcome the obstacles of CAR-NK cell therapy, both generally, and in cancers like T-cell lymphoma.
Collapse
Affiliation(s)
- Shaghayegh Khanmohammadi
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
39
|
Li X, Guo X, Huang J, Lin Q, Qin B, Jiang M, Shan X, Luo Z, Zhang J, Shi Y, Lu Y, Liu X, Du Y, Yang F, Luo L, You J. Recruiting T cells and sensitizing tumors to NKG2D immune surveillance for robust antitumor immune response. J Control Release 2023; 353:943-955. [PMID: 36535542 DOI: 10.1016/j.jconrel.2022.12.032] [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: 09/06/2022] [Revised: 12/08/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022]
Abstract
Although recruiting T cells to convert cold tumors into hot can prevent some tumors from evading immune surveillance, tumors have evolved more mechanisms to achieve immune evasion, such as downregulating major histocompatibility complex I (MHC I) molecules expression to prevent T cells from recognizing tumor-antigens, or secreting immune suppression cytokines that disable T cells. Tumor immune evasion not only promotes tumor growth, but also weakens the efficacy of existing tumor immunotherapies. Therefore, recruiting T cells while reshaping innate immunity plays an important role in preventing tumor immune escape. In this study, we constructed a long-acting in situ forming implant (ISFI) based on the Atrigel technology, co-encapsulated with G3-C12 and sulfisoxazole (SFX) as a drug depot in the tumor site (SFX + G3-C12-ISFI). First, G3-C12 could recruit T cells, and transform cold into hot tumors. Furthermore, SFX could inhibit tumor-derived exosomes secretion, reduce the shedding of NKG2D ligand (NKG2DL), repair NKG2D/NKG2DL pathway, reinvigorate natural killer (NK) cells, and evade the effects of MHC I molecules missing. In the humanized cold tumor model, our strategy showed an excellent anti-tumor effect, providing a smart strategy for solving tumor evasion immune surveillance.
Collapse
Affiliation(s)
- Xiang Li
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Xuemeng Guo
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Jiaxin Huang
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Qing Lin
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Bing Qin
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Mengshi Jiang
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Xinyu Shan
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Zhenyu Luo
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Junlei Zhang
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Yingying Shi
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Yichao Lu
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Xu Liu
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Yongzhong Du
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China
| | - Fuchun Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, PR China.
| | - Lihua Luo
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China.
| | - Jian You
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China.
| |
Collapse
|
40
|
Xiao H, Ye X, Vishwakarma V, Preet R, Dixon DA. CRC-derived exosomes containing the RNA binding protein HuR promote lung cell proliferation by stabilizing c-Myc mRNA. Cancer Biol Ther 2022; 23:139-149. [PMID: 35130122 PMCID: PMC8824215 DOI: 10.1080/15384047.2022.2034455] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
HuR overexpression is related to poor survival in patients with colon cancer. HuR overexpression leads to stabilization of tumor-promoting mRNAs by binding to 3′UTR-resident AREs. Exosomes, nanosized lipid bilayer vesicles, mediate many steps in cancer progression. The potential role of exosomal HuR in colon cancer lung metastasis is unclear. HuR expression was assessed immunohistochemically in tumor tissue samples from 20 patients with metastatic or nonmetastatic colon cancer and colon cancer lung metastasis and benign lung disease samples from ten patients. Exosomes were isolated from HCT116 WT and HuR KO colon cancer cells, and uptake of PKH67- and PKH26-labeled exosomes by BEAS-2B cells was evaluated using fluorescence and confocal microscopy. C-Myc and p21protein and mRNA levels were measured by western blotting and RT-qPCR, respectively. In clinical patients, HuR overexpression was significantly enhanced in colon tissues of patients with lung metastasis. HuR expression was higher in lung tissue with metastasis of colonic origin than with benign lung disease. The effect of HuR-containing CRC exosomes compared to HuR-deficient exosomes on wound closure was observed as enhanced proliferation. BEAS-2B cell migration and invasion were enhanced after HuR-containing exosomes treatment. BEAS-2B cells showed similar uptake of PKH67 (HCT116 WT)- and PKH26 (HCT116 HuR KO)-labeled exosomes. Exosomal HuR stabilized c-Myc mRNA and downregulated p21 expression, leading to G1/S transition, in human bronchial epithelial cells. HuR overexpression is associated with lung metastasis in colon cancer patients. Exosomal HuR derived from colon cancer cells alter the biological effect on normal lung epithelial cells.
Collapse
Affiliation(s)
- Hui Xiao
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.,Department of Molecular Biosciences, University of Kansas Cancer Center, University of Kansas, Lawrence, Kansas, USA
| | - Xiong Ye
- College of Clinical Medicine, Shanghai University of Medicine & Health Science, Shanghai, China
| | - Vikalp Vishwakarma
- Department of Molecular Biosciences, University of Kansas Cancer Center, University of Kansas, Lawrence, Kansas, USA
| | - Ranjan Preet
- Department of Molecular Biosciences, University of Kansas Cancer Center, University of Kansas, Lawrence, Kansas, USA
| | - Dan A Dixon
- Department of Molecular Biosciences, University of Kansas Cancer Center, University of Kansas, Lawrence, Kansas, USA
| |
Collapse
|
41
|
Secchiari F, Nuñez SY, Sierra JM, Ziblat A, Regge MV, Raffo Iraolagoitia XL, Rovegno A, Ameri C, Secin FP, Richards N, Ríos Pita H, Vitagliano G, Rico L, Mieggi M, Frascheri F, Bonanno N, Blas L, Trotta A, Friedrich AD, Fuertes MB, Domaica CI, Zwirner NW. The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology. Oncoimmunology 2022; 11:2104991. [PMID: 35936986 PMCID: PMC9354769 DOI: 10.1080/2162402x.2022.2104991] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
NKG2D is a major natural killer (NK) cell-activating receptor that recognizes eight ligands (NKG2DLs), including MICA, and whose engagement triggers NK cell effector functions. As NKG2DLs are upregulated on tumor cells but tumors can subvert the NKG2D-NKG2DL axis, NKG2DLs constitute attractive targets for antibody (Ab)-based immuno-oncology therapies. However, such approaches require a deep characterization of NKG2DLs and NKG2D cell surface expression on primary tumor and immune cells. Here, using a bioinformatic analysis, we observed that MICA is overexpressed in renal cell carcinoma (RCC), and we also detected an association between the NKG2D-MICA axis and a diminished overall survival of RCC patients. Also, by flow cytometry (FC), we observed that MICA was the only NKG2DL over-expressed on clear cell renal cell carcinoma (ccRCC) tumor cells, including cancer stem cells (CSC) that also coexpressed NKG2D. Moreover, tumor-infiltrating leukocytes (TIL), but not peripheral blood lymphoid cells (PBL) from ccRCC patients, over-expressed MICA, ULBP3 and ULBP4. In addition, NKG2D was downregulated on peripheral blood NK cells (PBNK) from ccRCC patients but upregulated on tumor-infiltrating NK cells (TINK). These TINK exhibited impaired degranulation that negatively correlated with NKG2D expression, diminished IFN-γ production, upregulation of TIM-3, and an impaired glucose intake upon stimulation with cytokines, indicating that they are dysfunctional, display features of exhaustion and an altered metabolic fitness. We conclude that ccRCC patients exhibit a distorted MICA-NKG2D axis, and MICA emerges as the forefront NKG2DL for the development of targeted therapies in ccRCC.
Collapse
Affiliation(s)
- Florencia Secchiari
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - Sol Yanel Nuñez
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - Jessica Mariel Sierra
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - Andrea Ziblat
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - María Victoria Regge
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - Ximena Lucía Raffo Iraolagoitia
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - Agustín Rovegno
- Servicio de Urología, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC)
| | - Carlos Ameri
- Servicio de Urología, Hospital Alemán, Buenos Aires, Argentina
| | - Fernando Pablo Secin
- Servicio de Urología, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC)
| | - Nicolás Richards
- Servicio de Urología, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC)
| | | | | | - Luis Rico
- Servicio de Urología, Hospital Alemán, Buenos Aires, Argentina
| | - Mauro Mieggi
- Servicio de Urología, Hospital Alemán, Buenos Aires, Argentina
| | | | - Nicolás Bonanno
- Servicio de Urología, Hospital Alemán, Buenos Aires, Argentina
| | - Leandro Blas
- Servicio de Urología, Hospital Alemán, Buenos Aires, Argentina
| | - Aldana Trotta
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - Adrián David Friedrich
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - Mercedes Beatriz Fuertes
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - Carolina Inés Domaica
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
| | - Norberto Walter Zwirner
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Argentina
- Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Universidad de Buenos Aires, Argentina
| |
Collapse
|
42
|
Shang S, Liu J, Hua F. Protein acylation: mechanisms, biological functions and therapeutic targets. Signal Transduct Target Ther 2022; 7:396. [PMID: 36577755 PMCID: PMC9797573 DOI: 10.1038/s41392-022-01245-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 09/27/2022] [Accepted: 11/06/2022] [Indexed: 12/30/2022] Open
Abstract
Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With the progress of metabonomics and proteomics, metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or deacylases. Reciprocally, protein acylation is involved in key cellular processes relevant to physiology and diseases, such as protein stability, protein subcellular localization, enzyme activity, transcriptional activity, protein-protein interactions and protein-DNA interactions. Herein, we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several diseases. We also highlight the recent progress in the development of inhibitors for acyltransferase, deacylase, and acylation reader proteins for their potential applications in drug discovery.
Collapse
Affiliation(s)
- Shuang Shang
- grid.506261.60000 0001 0706 7839CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050 Beijing, P.R. China
| | - Jing Liu
- grid.506261.60000 0001 0706 7839CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050 Beijing, P.R. China
| | - Fang Hua
- grid.506261.60000 0001 0706 7839CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050 Beijing, P.R. China
| |
Collapse
|
43
|
Tumor-Derived Extracellular Vesicles in Cancer Immunoediting and Their Potential as Oncoimmunotherapeutics. Cancers (Basel) 2022; 15:cancers15010082. [PMID: 36612080 PMCID: PMC9817790 DOI: 10.3390/cancers15010082] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
The tumor microenvironment (TME) within and around a tumor is a complex interacting mixture of tumor cells with various stromal cells, including endothelial cells, fibroblasts, and immune cells. In the early steps of tumor formation, the local microenvironment tends to oppose carcinogenesis, while with cancer progression, the microenvironment skews into a protumoral TME and the tumor influences stromal cells to provide tumor-supporting functions. The creation and development of cancer are dependent on escape from immune recognition predominantly by influencing stromal cells, particularly immune cells, to suppress antitumor immunity. This overall process is generally called immunoediting and has been categorized into three phases; elimination, equilibrium, and escape. Interaction of tumor cells with stromal cells in the TME is mediated generally by cell-to-cell contact, cytokines, growth factors, and extracellular vesicles (EVs). The least well studied are EVs (especially exosomes), which are nanoparticle-sized bilayer membrane vesicles released by many cell types that participate in cell/cell communication. EVs carry various proteins, nucleic acids, lipids, and small molecules that influence cells that ingest the EVs. Tumor-derived extracellular vesicles (TEVs) play a significant role in every stage of immunoediting, and their cargoes change from immune-activating in the early stages of immunoediting into immunosuppressing in the escape phase. In addition, their cargos change with different treatments or stress conditions and can be influenced to be more immune stimulatory against cancer. This review focuses on the emerging understanding of how TEVs affect the differentiation and effector functions of stromal cells and their role in immunoediting, from the early stages of immunoediting to immune escape. Consideration of how TEVs can be therapeutically utilized includes different treatments that can modify TEV to support cancer immunotherapy.
Collapse
|
44
|
Feng L, Guo L, Tanaka Y, Su L. Tumor-Derived Small Extracellular Vesicles Involved in Breast Cancer Progression and Drug Resistance. Int J Mol Sci 2022; 23:ijms232315236. [PMID: 36499561 PMCID: PMC9736664 DOI: 10.3390/ijms232315236] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/28/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Breast cancer is one of the most serious and terrifying threats to the health of women. Recent studies have demonstrated that interaction among cancer cells themselves and those with other cells, including immune cells, in a tumor microenvironment potentially and intrinsically regulate and determine cancer progression and metastasis. Small extracellular vesicles (sEVs), a type of lipid-bilayer particles derived from cells, with a size of less than 200 nm, are recognized as one form of important mediators in cell-to-cell communication. sEVs can transport a variety of bioactive substances, including proteins, RNAs, and lipids. Accumulating evidence has revealed that sEVs play a crucial role in cancer development and progression, with a significant impact on proliferation, invasion, and metastasis. In addition, sEVs systematically coordinate physiological and pathological processes, such as coagulation, vascular leakage, and stromal cell reprogramming, to bring about premetastatic niche formation and to determine metastatic organ tropism. There are a variety of oncogenic factors in tumor-derived sEVs that mediate cellular communication between local stromal cells and distal microenvironment, both of which are important in cancer progression and metastasis. Tumor-derived sEVs contain substances that are similar to parental tumor cells, and as such, sEVs could be biomarkers in cancer progression and potential therapeutic targets, particularly for predicting and preventing future metastatic development. Here, we review the mechanisms underlying the regulation by tumor-derived sEVs on cancer development and progression, including proliferation, metastasis, drug resistance, and immunosuppression, which coordinately shape the pro-metastatic microenvironment. In addition, we describe the application of sEVs to the development of cancer biomarkers and potential therapeutic modalities and discuss how they can be engineered and translated into clinical practice.
Collapse
Affiliation(s)
- Lingyun Feng
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Lijuan Guo
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yoshimasa Tanaka
- Center for Medical Innovation, Nagasaki University, 1-7-1, Sakamoto, Nagasaki 852-8588, Japan
- Correspondence: (Y.T.); (L.S.); Tel.: +81-95-819-7063 (Y.T.); +86-27-8779-2024 (L.S.); Fax: +81-95-819-2189 (Y.T.); +86-27-8779-2072 (L.S.)
| | - Li Su
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- Correspondence: (Y.T.); (L.S.); Tel.: +81-95-819-7063 (Y.T.); +86-27-8779-2024 (L.S.); Fax: +81-95-819-2189 (Y.T.); +86-27-8779-2072 (L.S.)
| |
Collapse
|
45
|
Wang G, Luo G, Zhao M, Miao H. Significance of exosomes in hepatocellular carcinoma. Front Oncol 2022; 12:1056379. [PMID: 36531059 PMCID: PMC9748478 DOI: 10.3389/fonc.2022.1056379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/11/2022] [Indexed: 09/28/2023] Open
Abstract
Among the most prevalent cancers in the world, hepatocellular carcinoma (HCC) has a high mortality rate. The diagnosis and management of HCC are presently hindered by difficulties in early detection and suboptimal treatment outcomes. Exosomes have been shown to play an important role in hepatocarcinogenesis and can also be used for diagnosis and treatment. In this review, we discussed the research progress on exosomes in hepatocarcinogenesis development, tumor microenvironment remodeling, treatment resistance, and immunosuppression. HCC can be diagnosed and treated by understanding the pathogenesis and identifying early diagnostic markers. This review will be a significant reference for scholars with an initial understanding of the field to fully understand the role of exosomes in the organism.
Collapse
Affiliation(s)
- GuoYun Wang
- Department of Hepatobiliary Surgery, The Second Hospital of Guangdong Medical University, Zhanjiang, China
| | - GaiXiang Luo
- The First Clinical Medical College of Lanzhou University, Gansu Provincial People’s Hospital, Lanzhou, China
| | - MeiJing Zhao
- Department of Hepatobiliary Surgery, The Second Hospital of Guangdong Medical University, Zhanjiang, China
| | - HuiLai Miao
- Department of Hepatobiliary Surgery, The Second Hospital of Guangdong Medical University, Zhanjiang, China
- Key Laboratory of Liver Injury Diagnosis and Repair, Guangdong Medical University, Zhanjiang, China
| |
Collapse
|
46
|
Reale A, Khong T, Spencer A. Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment. J Clin Med 2022; 11:jcm11236892. [PMID: 36498469 PMCID: PMC9737553 DOI: 10.3390/jcm11236892] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/15/2022] [Accepted: 11/15/2022] [Indexed: 11/24/2022] Open
Abstract
Tumor cells actively incorporate molecules (e.g., proteins, lipids, RNA) into particles named extracellular vesicles (EVs). Several groups have demonstrated that EVs can be transferred to target (recipient) cells, making EVs an important means of intercellular communication. Indeed, EVs are able to modulate the functions of target cells by reprogramming signaling pathways. In a cancer context, EVs promote the formation of a supportive tumor microenvironment (TME) and (pre)metastatic niches. Recent studies have revealed that immune cells, tumor cells and their secretome, including EVs, promote changes in the TME and immunosuppressive functions of immune cells (e.g., natural killer, dendritic cells, T and B cells, monocytes, macrophages) that allow tumor cells to establish and propagate. Despite the growing knowledge on EVs and on their roles in cancer and as modulators of the immune response/escape, the translation into clinical practice remains in its early stages, hence requiring improved translational research in the EVs field. Here, we comprehensively review the current knowledge and most recent research on the roles of EVs in tumor immune evasion and immunosuppression in both solid tumors and hematological malignancies. We also highlight the clinical utility of EV-mediated immunosuppression targeting and EV-engineering. Importantly, we discuss the controversial role of EVs in cancer biology, current limitations and future perspectives to further the EV knowledge into clinical practice.
Collapse
Affiliation(s)
- Antonia Reale
- Myeloma Research Group, Australian Centre for Blood Diseases, Central Clinical School, Monash University—Alfred Health, Melbourne, VIC 3004, Australia
- Correspondence: (A.R.); (A.S.)
| | - Tiffany Khong
- Myeloma Research Group, Australian Centre for Blood Diseases, Central Clinical School, Monash University—Alfred Health, Melbourne, VIC 3004, Australia
| | - Andrew Spencer
- Myeloma Research Group, Australian Centre for Blood Diseases, Central Clinical School, Monash University—Alfred Health, Melbourne, VIC 3004, Australia
- Malignant Haematology and Stem Cell Transplantation, Department of Haematology, Alfred Hospital, Melbourne, VIC 3004, Australia
- Department of Clinical Hematology, Monash University, Melbourne, VIC 3004, Australia
- Correspondence: (A.R.); (A.S.)
| |
Collapse
|
47
|
Guan MC, Wang MD, Wang WY, Li C, Yao LQ, Zhu H, Yang T. Exosomes as mediators of tumor immune escape and immunotherapy in hepatocellular carcinoma. LIVER RESEARCH 2022; 6:132-138. [PMID: 39958202 PMCID: PMC11791807 DOI: 10.1016/j.livres.2022.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 07/16/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC), a typical inflammatory-related cancer, mainly occurs in patients with chronic liver diseases. Moreover, the liver is an immunologically privileged apparatus with multiple immunosuppressive cell groups. The long process of inflammation-mediated carcinogenesis turns the HCC tumor microenvironment (TME) into one with strong immunosuppression, facilitating the immune escape of HCC cells. Accumulated data have manifested that tumor-associated cell-derived exosomes carry diverse molecular cargoes (e.g., proteins and nucleic acids) for mediating cell-to-cell communication and are implicated in TME remodeling to promote tumor-infiltrating immune cell reprogramming, ultimately creating a tumor-friendly microenvironment. Characterized by several intrinsic attributes, such as good stability (bilayer-like structure) and high biocompatibility (cell secretion), exosomes can be modified or engineered as nanocarriers to deliver tumor-specific antigens or antitumor drugs to targeted cells or organs, thus effectively triggering the HCC cell elimination by the immune system. This review aimed to highlight the pivotal role of exosomes in regulating immune escape mechanisms in HCC and recent advances in exosome-mediated immunotherapy for HCC.
Collapse
Affiliation(s)
- Ming-Cheng Guan
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Wan-Yin Wang
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Hong Zhu
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
| |
Collapse
|
48
|
Jangholi A, Müller Bark J, Kenny L, Vasani S, Rao S, Dolcetti R, Punyadeera C. Exosomes at the crossroad between therapeutic targets and therapy resistance in head and neck squamous cell carcinoma. Biochim Biophys Acta Rev Cancer 2022; 1877:188784. [PMID: 36028150 DOI: 10.1016/j.bbcan.2022.188784] [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: 06/15/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/24/2022]
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are aggressive and clinically challenging tumours that require a multidisciplinary management approach. Despite significant therapy improvements, HNSCC patients have a poor prognosis with a 5-year survival rate of about 65%. As recently recognised key players in cancer, exosomes are extracellular vesicles (EVs) with a diameter of nearly 50-120 nm which transport information from one cell to another. Exosomes are actively involved in various aspects of tumour initiation, development, metastasis, immune regulation, therapy resistance, and therapeutic applications. However, current knowledge of the role of exosomes in the pathophysiological processes of HNSCC is still in its infancy, and additional studies are needed. In this review, we summarise and discuss the relevance of exosomes in mediating local immunosuppression and therapy resistance of HNSCC. We also review the most recent studies that have explored the therapeutic potential of exosomes as cancer vaccines, drug carriers or tools to reverse the drug resistance of HNSCC.
Collapse
Affiliation(s)
- Abolfazl Jangholi
- Centre for Biomedical Technologies, The School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, QLD, Australia; The School of Environment and Science, Griffith Institute for Drug Discovery (GRIDD), Griffith University, Brisbane, Australia
| | - Juliana Müller Bark
- The School of Environment and Science, Griffith Institute for Drug Discovery (GRIDD), Griffith University, Brisbane, Australia
| | - Lizbeth Kenny
- Royal Brisbane and Women's Hospital, Cancer Care Services, Herston, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Sarju Vasani
- Royal Brisbane and Women's Hospital, Cancer Care Services, Herston, Australia; Department of Otolaryngology, Royal Brisbane and Women's Hospital, Herston, Australia
| | - Sudha Rao
- Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Riccardo Dolcetti
- Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Australia; Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia; The University of Queensland Diamantina Institute, Brisbane, QLD, Australia
| | - Chamindie Punyadeera
- The School of Environment and Science, Griffith Institute for Drug Discovery (GRIDD), Griffith University, Brisbane, Australia; Menzies Health Institute Queensland (MIHQ), Griffith University, Gold Coast, Australia.
| |
Collapse
|
49
|
Dieterich LC. Mechanisms of extracellular vesicle-mediated immune evasion in melanoma. Front Immunol 2022; 13:1002551. [PMID: 36081494 PMCID: PMC9445580 DOI: 10.3389/fimmu.2022.1002551] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
Melanoma-derived extracellular vesicles (EVs) have been found to promote tumor growth and progression, and to predict patient responsiveness to immunotherapy. Consequently, EVs have been implicated in tumor immune evasion, and multiple studies reported immune-regulatory activities of melanoma EVs in vitro and in vivo. This review highlights mechanistic insights in EV-mediated regulation of various immune cell types, including effects on inflammatory, apoptotic, stress-sensing and immune checkpoint pathways as well as antigen-dependent responses. Additionally, current challenges in the field are discussed that need to be overcome to determine the clinical relevance of these various mechanisms and to develop corresponding therapeutic approaches to promote tumor immunity and immunotherapy responsiveness in melanoma patients in the future.
Collapse
|
50
|
Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands. Nat Commun 2022; 13:4795. [PMID: 35970825 PMCID: PMC9378736 DOI: 10.1038/s41467-022-32311-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 07/26/2022] [Indexed: 11/17/2022] Open
Abstract
Glioblastoma (GBM) is a highly aggressive primary brain tumour and is resistant to nearly all available treatments, including natural killer (NK) cell immunotherapy. However, the factors mediating NK cell evasion in GBM remain largely unclear. Here, we report that EZH2-92aa, a protein encoded by circular EZH2, is overexpressed in GBM and induces the immune evasion of GBM stem cells (GSCs) from NK cells. Positively regulated by DEAD-box helicase 3 (DDX3), EZH2-92aa directly binds the major histocompatibility complex class I polypeptide-related sequence A/B (MICA/B) promoters and represses their transcription; it also indirectly represses UL16-binding protein (ULBP) transcription by stabilizing EZH2. The downregulation of NK group 2D ligands (NKG2DLs, including MICA/B and ULBPs) in GSCs mediates NK cell resistance. Moreover, stable EZH2-92aa knockdown enhances NK cell-mediated GSC eradication in vitro and in vivo and synergizes with anti-PD1 therapy. Our results highlight the immunosuppressive function of EZH2-92aa in inhibiting the NK cell response in GBM and the clinical potential of targeting EZH2-92aa for NK-cell-directed immune therapy. Glioblastoma (GBM) is a highly aggressive brain tumor, frequently resistant to therapies, including natural killer (NK) cell based immunotherapy. Here, the authors show that the circular RNA EZH2 is highly expressed in GBM and encodes the peptide EZH2-92aa, whose expression is associated with inhibition of NK cell cytotoxicity.
Collapse
|