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Haręża DA, Kania KD, Jarych D, Wilczyński JR, Wilczyński M, Malinowski A, Paradowska E. TLR8 and TLR9 gene polymorphisms and the risk of high-grade serous ovarian cancer. Int J Biol Macromol 2025; 313:144259. [PMID: 40381782 DOI: 10.1016/j.ijbiomac.2025.144259] [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: 07/19/2024] [Revised: 04/23/2025] [Accepted: 05/14/2025] [Indexed: 05/20/2025]
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most prevalent and lethal histotype of epithelial ovarian cancer (EOC). Single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes may serve as important markers of susceptibility to numerous cancers. We explored the frequency of TLR8 and TLR9 polymorphisms in 325 women and determined their role in susceptibility to EOC and viral infection. The group of patients with EOC included 93 HGSOC and 32 non-HGSOC cases. TLR8 rs3764879, TLR8 rs3764880, TLR9 rs352139, and rs352140 SNPs were genotyped using the allelic discrimination method. The homozygous recessive genotypes for TLR8 rs3764879 and TLR9 rs352139 SNPs were more common in patients with EOC, compared to healthy women, and increased the risk of ovarian cancer (p = 0.0001 and p < 0.05, respectively). The TLR8 rs3764879 SNP reached statistical significance after Bonferroni's correction for multiple tests. The homozygous recessive genotype for TLR8 rs3764879 (-129C>G) was associated with a five-fold increased risk of HGSOC (p = 0.0001). A mutation in at least one allele of the TLR8 rs3764879 was also associated with a higher level of TLR8 expression in tumor tissues (p = 0.0008). The present study demonstrated a strong association between the TLR8 -129C>G SNP and an increased risk of the HGSOC subtype.
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Affiliation(s)
- Daria A Haręża
- Laboratory of Virology, The Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland; BioMedChem Doctoral School of the University of Lodz and the Institutes of the Polish Academy of Sciences in Lodz, Lodz 90-136, Poland
| | - Katarzyna D Kania
- Laboratory of Virology, The Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland; Department of Diagnostic Techniques in Pathomorphology, Medical University of Lodz, Lodz 92-213, Poland
| | - Dariusz Jarych
- Laboratory of Virology, The Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland
| | - Jacek R Wilczyński
- Department of Surgical and Oncological Gynecology, Medical University of Lodz, Lodz 92-213, Poland; Department of Gynecology and Obstetrics, Tomaszow Health Center, Tomaszow Mazowiecki 97-200, Poland
| | - Miłosz Wilczyński
- Department of Surgical, Endoscopic and Oncological Gynecology, Polish Mother's Health Center Research Institute, Lodz 93-338, Poland
| | - Andrzej Malinowski
- Department of Surgical, Endoscopic and Oncological Gynecology, Polish Mother's Health Center Research Institute, Lodz 93-338, Poland
| | - Edyta Paradowska
- Laboratory of Virology, The Institute of Medical Biology, Polish Academy of Sciences, Lodz 93-232, Poland.
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Kakh M, Doroudchi M, Talepoor A. Induction of Regulatory T Cells After Virus Infection and Vaccination. Immunology 2025. [PMID: 40329764 DOI: 10.1111/imm.13927] [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: 09/24/2024] [Revised: 03/04/2025] [Accepted: 03/17/2025] [Indexed: 05/08/2025] Open
Abstract
Vaccines have been proven to be one of the safest and most effective ways to prevent and combat diseases. However, the main focus has been on the evaluation of the potency of effector mechanisms and the lack of adverse effects of vaccine candidates. Recently, the importance of induced regulatory mechanisms of the immune system after vaccination has come to light. With the increase in our knowledge about these regulatory mechanisms including the regulatory T cells (Tregs), we have come to understand the significance of this arm of the immune system in controlling immunopathology and/or diminishing the effectiveness of vaccines, especially viral vaccines. Tregs play a dual role during infectious diseases by limiting immune-mediated pathology and also contributing to chronic pathogen persistence by decreasing effector immunity and clearance of infection. Tregs may also affect immune responses after vaccination primarily by inhibiting antigen presenting cell function such as cytokine secretion and co-stimulatory molecule expression as well as effector T (Teff) and B cell function. In this article, we review the current knowledge on the induction of Tregs after several life-threatening virus infections and their available vaccines to bring them to the spotlight and emphasise that studying viral-induced antigen-specific Tregs will help us improve the effectiveness and decrease the immunopathology or side effects of viral vaccines. Trial Registration: ClinicalTrials.gov identifier: NCT04357444.
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Affiliation(s)
- MansourehKarimi Kakh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - AtefeGhamar Talepoor
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Zhang R, Song Y, Yao J, Qin H, Ye Y, Gao J, Zhang C, Han D, Gao M, Chen H, Chen X, Zhao S, Liu K, Tu Y, Xu Z. RNA-Seq Reveals the Mechanism of Synergistic Hydrogen-Chemotherapy Based on Active Magnesium Micromotors for Inhibiting Glioblastoma Recurrence by Modulating Tumor Microenvironment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2408809. [PMID: 40259480 DOI: 10.1002/smll.202408809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 02/24/2025] [Indexed: 04/23/2025]
Abstract
Postoperative recurrence of glioblastoma (GBM) is a key contributing factor to the unfavorable prognosis of patients. Chemotherapy has been extensively employed as a postoperative treatment for GBM; however, the produced drug resistance significantly undermines the chemotherapeutic efficacy. Herein, a multifunctional system based on magnesium micromotor (Mg-Motor-DOX) is designed and fabricated that can generate hydrogen gas in situ and actively deliver the chemotherapeutic drug doxorubicin (DOX). Utilizing a temperature-sensitive hydrogel, Mg-Motor-DOX is administrated in situ to the residual cavity of the tumor after subtotal GBM resection. The produced H2 by the Mg-water reaction not only propels the motion of motors but also functions as an antioxidant to effectively alleviate the neuroinflammation caused by GBM resection. The H2 bubbles create a pronounced vortex flow in situ, greatly enhancing the DOX penetration and the sensitivity of GBM cells to DOX. Therefore, synergistic hydrogen-chemotherapy significantly inhibits the recurrence of the in situ GBM model. RNA-Seq technology further elucidates the role of the strategy in modulating the tumor immune microenvironment via converting cold tumors into hot tumors, thereby establishing a theoretical foundation for the clinical implementation of synergistic hydrogen-chemotherapy.
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Affiliation(s)
- Ruotian Zhang
- Department of Ultrasound, Institute of Ultrasound in Musculoskeletal Sports Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, China
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Yanzhen Song
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Jiawei Yao
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Hanfeng Qin
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Yicheng Ye
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Junbin Gao
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Cheng Zhang
- University of Toronto Scarborough, 1265 Military Trail, Scarborough, ON, M1C 1A4, Canada
| | - Dayong Han
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Ming Gao
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Hao Chen
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xin Chen
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Shiguang Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Kun Liu
- Experimental Education/Administration Center, National Demonstration Center for Experimental Education of Basic Medical Sciences, Key Laboratory of Functional Proteomics of Guangdong Province, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Yingfeng Tu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zhili Xu
- Department of Ultrasound, Institute of Ultrasound in Musculoskeletal Sports Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, China
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Patra S, Chaudhary S, Samal SC, Ayyanar P, Padhi S, Nayak HK, Satapathy AK, Nayak S, Sahu A, Parida T, Shahin M. FoxP3-positive T regulatory cells and its effector mechanisms in Crohn's disease: an immunohistochemical and image morphometric analysis on endoscopic mucosal biopsies. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00509. [PMID: 40207496 DOI: 10.1097/meg.0000000000002971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
OBJECTIVE Crohn's disease (CD) is an immune inflammatory disorder of the gastrointestinal tract arising from a complex interplay of genetic, environmental, microbiome, and immune factors. Regulatory T cells (Tregs), characterized by FoxP3 expression, are crucial for maintaining immune homeostasis through PD-1/PD-L1 interaction, interleukin (IL)-10 release, and granzyme (GrB) production. This study aimed to elucidate the role of FoxP3 positive (+) Tregs in CD. METHODS Segmental colonoscopic biopsies from 46 treatment-naive CD cases (34 adults and 12 children) categorized into noninflamed [n = 32; Nancy histologic index (NHI) 0, 1] and inflamed (n = 100; NHI 2-4) mucosae using NHI. CD4, FoxP3, PD-1, IL-10, and GrB immunoexpression were analyzed by eyeballing and image morphometry. Findings were correlated with activity, granulomas, and skip lesions; and compared with site-matched non-inflammatory bowel disease (IBD) controls (n = 30). RESULTS FoxP3+ Tregs, IL-10, PD-1, and GrB expressions were significantly higher in NHI 3-4 mucosae than in NHI 0-1 and controls (P < 0.05). No significant differences were observed between adults and children, whereas those with granulomas had increased expression (P = 0.045). The FoxP3 : CD4 ratio positively correlated with IL-10 (Spearman, r = 0.307, P = 0.002), GrB (r = 0.302, P = 0.002), but not with PD-1 (r = 0.98, P = 0.33). CONCLUSIONS Our findings point to the possibility of a qualitative defect in FoxP3+ Tregs in CD. The functional arms of Tregs in CD need to be elucidated further in larger prospective cohorts to validate our observations and pave the way for future immunotherapy.
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Affiliation(s)
| | | | | | | | | | | | | | - Saurav Nayak
- Department of Biochemistry, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Ajit Sahu
- Department of Pathology and Laboratory Medicine
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Soe YM, Sim SL, Kumari S. Innate Immune Sensors and Cell Death-Frontiers Coordinating Homeostasis, Immunity, and Inflammation in Skin. Viruses 2025; 17:241. [PMID: 40006996 PMCID: PMC11861910 DOI: 10.3390/v17020241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 02/05/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
The skin provides a life-sustaining interface between the body and the external environment. A dynamic communication among immune and non-immune cells in the skin is essential to ensure body homeostasis. Dysregulated cellular communication can lead to the manifestation of inflammatory skin conditions. In this review, we will focus on the following two key frontiers in the skin: innate immune sensors and cell death, as well as their cellular crosstalk in the context of skin homeostasis and inflammation. This review will highlight the recent advancements and mechanisms of how these pathways integrate signals and orchestrate skin immunity, focusing on inflammatory skin diseases and skin infections in mice and humans.
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Affiliation(s)
| | | | - Snehlata Kumari
- Frazer Institute, The University of Queensland, Dermatology Research Centre, Woolloongabba, Brisbane, QLD 4102, Australia; (Y.M.S.); (S.L.S.)
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Khan S, Simsek R, Fuentes JDB, Vohra I, Vohra S. Implication of Toll-Like Receptors in growth and management of health and diseases: Special focus as a promising druggable target to Prostate Cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189229. [PMID: 39608622 DOI: 10.1016/j.bbcan.2024.189229] [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: 07/01/2024] [Revised: 11/18/2024] [Accepted: 11/24/2024] [Indexed: 11/30/2024]
Abstract
Toll-like receptors (TLRs) are protein structures belonging to the pattern recognition receptors family. TLRs have the great potential that can directly recognize the specific molecular structures on the surface of pathogens, damaged senescent cells and apoptotic host cells. Available evidence suggests that TLRs have crucial roles in maintaining tissue homeostasis through control of the inflammatory and tissue repair responses during injury. TLRs are the player of first line of defense against different microbes and activate the signaling cascades which help to induce the immune system and inflammatory responses by affecting various signaling pathways, including nuclear factor-κB (NF-κB), interferon regulatory factors, and mitogen-activated protein kinases (MAPKs). TLRs have been identified to be over-expressed in different types of cancers and play an important role in control of health and management of diseases. The current review provides updated knowledge on the implication of TLRs in growth and management of cancers including prostate cancer.
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Affiliation(s)
- Shahanavaj Khan
- Department of Medical Lab Technology, Indian Institute of Health Technology (IIHT), Paramedical and Nursing College, Deoband, 247554 Saharanpur, India; Department of Health Sciences, Novel Global Community Educational Foundation, Australia.
| | - Rahime Simsek
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe Unversity, 06100 Ankara, Turkey
| | - Javier David Benitez Fuentes
- Medical Oncology Department, Hospital General Universitario de Elche, Carrer Almazara, 11, 03203 Elche, Alicante, Spain
| | - Isra Vohra
- University of Houston Clear Lake Graduated with bachelors Physiology, Houston, TX, USA
| | - Saeed Vohra
- Department of Anatomy and Physiology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
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7
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Trachuk KN, Pestov NB, Biryukova YK, Kolyasnikova NM. [The impact of innate immune response on the efficacy of oncolytic viruses]. Vopr Virusol 2024; 69:479-488. [PMID: 39841413 DOI: 10.36233/0507-4088-275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Indexed: 01/23/2025]
Abstract
Oncolytic viruses represent a promising class of immunotherapeutic agents for the treatment of malignant tumors. The proposed mechanism of action of various oncolytic viruses has initially been explained by the ability of such viruses to selectively lyse tumor cells without damaging healthy ones. Recently, there have emerged more studies determining the effect of the antiviral immunostimulating mechanisms on the effectiveness of treatment in cancer patients. Stimulation of innate immune cells by an oncolytic virus can initiate an adaptive antitumor immune response, yet at the same time, the antiviral mechanisms of the immune system can limit the spread of the virus, thereby reducing its effectiveness. Thus, the success of the clinical application of the oncolytic viruses directly depends on the three key components: tumor immunosuppression, antiviral responses, and antitumor immune responses. The review presents current data on the influence of pattern recognition receptors on the effectiveness of oncolytic viruses.
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Affiliation(s)
- K N Trachuk
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences (Institute of Poliomyelitis)
| | - N B Pestov
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences (Institute of Poliomyelitis)
| | - Y K Biryukova
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences (Institute of Poliomyelitis)
| | - N M Kolyasnikova
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences (Institute of Poliomyelitis)
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Zhang X, Goedegebuure SP, Chen MY, Mishra R, Zhang F, Yu YY, Singhal K, Li L, Gao F, Myers NB, Vickery T, Hundal J, McLellan MD, Sturmoski MA, Kim SW, Chen I, Davidson JT, Sankpal NV, Myles S, Suresh R, Ma CX, Foluso A, Wang-Gillam A, Davies S, Hagemann IS, Mardis ER, Griffith O, Griffith M, Miller CA, Hansen TH, Fleming TP, Schreiber RD, Gillanders WE. Neoantigen DNA vaccines are safe, feasible, and induce neoantigen-specific immune responses in triple-negative breast cancer patients. Genome Med 2024; 16:131. [PMID: 39538331 PMCID: PMC11562513 DOI: 10.1186/s13073-024-01388-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 09/20/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence. METHODS Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing. RESULTS Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4-20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7-100%) in the cohort of vaccinated patients. CONCLUSION Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses. CLINICAL TRIAL REGISTRATION NUMBER NCT02348320.
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Affiliation(s)
- Xiuli Zhang
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - S Peter Goedegebuure
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
| | - Michael Y Chen
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Rashmi Mishra
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Felicia Zhang
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Yik Yeung Yu
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Kartik Singhal
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Lijin Li
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Feng Gao
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Nancy B Myers
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Tammi Vickery
- Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Jasreet Hundal
- McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA
| | - Michael D McLellan
- McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA
| | - Mark A Sturmoski
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Samuel W Kim
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Ina Chen
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Jesse T Davidson
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Narendra V Sankpal
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Stephanie Myles
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
| | - Rama Suresh
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
| | - Cynthia X Ma
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
| | - Ademuyiwa Foluso
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
| | - Andrea Wang-Gillam
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
| | - Sherri Davies
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
| | - Ian S Hagemann
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Elaine R Mardis
- McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
- Current Affiliation: Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH, USA
| | - Obi Griffith
- McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA
| | - Malachi Griffith
- McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA
| | - Christopher A Miller
- McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA
| | - Ted H Hansen
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Timothy P Fleming
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
| | - Robert D Schreiber
- Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
| | - William E Gillanders
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA.
- The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA.
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9
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da Silva Barcelos L, Ford AK, Frühauf MI, Botton NY, Fischer G, Maggioli MF. Interactions Between Bovine Respiratory Syncytial Virus and Cattle: Aspects of Pathogenesis and Immunity. Viruses 2024; 16:1753. [PMID: 39599867 PMCID: PMC11598946 DOI: 10.3390/v16111753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/25/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
Bovine respiratory syncytial virus (BRSV) is a major respiratory pathogen in cattle and is relevant to the livestock industry worldwide. BRSV is most severe in young calves and is often associated with stressful management events. The disease is responsible for economic losses due to lower productivity, morbidity, mortality, and prevention and treatment costs. As members of the same genus, bovine and human RSV share a high degree of homology and are similar in terms of their genomes, transmission, clinical signs, and epidemiology. This overlap presents an opportunity for One Health approaches and translational studies, with dual benefits; however, there is still a relative lack of studies focused on BRSV, and the continued search for improved prophylaxis highlights the need for a deeper understanding of its immunological features. BRSV employs different host-immunity-escaping mechanisms that interfere with effective long-term memory responses to current vaccines and natural infections. This review presents an updated description of BRSV's immunity processes, such as the PRRs and signaling pathways involved in BRSV infection, aspects of its pathogeny, and the evading mechanisms developed by the virus to thwart the immune response.
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Affiliation(s)
- Lariane da Silva Barcelos
- Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078, USA; (L.d.S.B.)
- Laboratory of Virology and Immunology, Veterinary College, Universidade Federal de Pelotas, Capão do Leão, Rio Grande do Sul 96010, Brazil; (M.I.F.); (N.Y.B.); (G.F.)
| | - Alexandra K. Ford
- Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078, USA; (L.d.S.B.)
| | - Matheus Iuri Frühauf
- Laboratory of Virology and Immunology, Veterinary College, Universidade Federal de Pelotas, Capão do Leão, Rio Grande do Sul 96010, Brazil; (M.I.F.); (N.Y.B.); (G.F.)
| | - Nadalin Yandra Botton
- Laboratory of Virology and Immunology, Veterinary College, Universidade Federal de Pelotas, Capão do Leão, Rio Grande do Sul 96010, Brazil; (M.I.F.); (N.Y.B.); (G.F.)
| | - Geferson Fischer
- Laboratory of Virology and Immunology, Veterinary College, Universidade Federal de Pelotas, Capão do Leão, Rio Grande do Sul 96010, Brazil; (M.I.F.); (N.Y.B.); (G.F.)
| | - Mayara Fernanda Maggioli
- Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078, USA; (L.d.S.B.)
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Gomes FDC, Galhardo DDR, Navegante ACG, dos Santos GS, Dias HAAL, Dias Júnior JRL, Pierre ME, Luz MO, de Melo Neto JS. Bioinformatics analysis to identify the relationship between human papillomavirus-associated cervical cancer, toll-like receptors and exomes: A genetic epidemiology study. PLoS One 2024; 19:e0305760. [PMID: 39208235 PMCID: PMC11361573 DOI: 10.1371/journal.pone.0305760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 06/04/2024] [Indexed: 09/04/2024] Open
Abstract
INTRODUCTION Genetic variants may influence Toll-like receptor (TLR) signaling in the immune response to human papillomavirus (HPV) infection and lead to cervical cancer. In this study, we investigated the pattern of TLR expression in the transcriptome of HPV-positive and HPV-negative cervical cancer samples and looked for variants potentially related to TLR gene alterations in exomes from different populations. MATERIALS AND METHODS A cervical tissue sample from 28 women, which was obtained from the Gene Expression Omnibus database, was used to examine TLR gene expression. Subsequently, the transcripts related to the TLRs that showed significant gene expression were queried in the Genome Aggregation Database to search for variants in more than 5,728 exomes from different ethnicities. RESULTS Cancer and HPV were found to be associated (p<0.0001). TLR1(p = 0.001), TLR3(p = 0.004), TLR4(221060_s_at)(p = 0.001), TLR7(p = 0.001;p = 0.047), TLR8(p = 0.002) and TLR10(p = 0.008) were negatively regulated, while TLR4(1552798_at)(p<0.0001) and TLR6(p = 0.019) were positively regulated in HPV-positive patients (p<0.05). The clinical significance of the variants was statistically significant for TLR1, TLR3, TLR6 and TLR8 in association with ethnicity. Genetic variants in different TLRs have been found in various ethnic populations. Variants of the TLR gene were of the following types: TLR1(5_prime_UTR), TLR4(start_lost), TLR8(synonymous;missense) and TLR10(3_prime_UTR). The "missense" variant was found to have a risk of its clinical significance being pathogenic in South Asian populations (OR = 56,820[95%CI:40,206,80,299]). CONCLUSION The results of this study suggest that the variants found in the transcriptomes of different populations may lead to impairment of the functional aspect of TLRs that show significant gene expression in cervical cancer samples caused by HPV.
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Affiliation(s)
- Fabiana de Campos Gomes
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
- Faculty of Medicine CERES (FACERES), São José do Rio Preto, São Paulo, Brazil
| | - Deizyane dos Reis Galhardo
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | | | - Gabriela Sepêda dos Santos
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | | | - José Ribamar Leal Dias Júnior
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | - Marie Esther Pierre
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | - Marlucia Oliveira Luz
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
| | - João Simão de Melo Neto
- Postgraduate Program in Collective Health in the Amazon (PPGSCA), Federal University of Pará (UFPA), Belém, Pará, Brazil
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11
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Zhou Y, Gong J, Deng X, Shen L, Liu L. Novel insights: crosstalk with non-puerperal mastitis and immunity. Front Immunol 2024; 15:1431681. [PMID: 39148739 PMCID: PMC11324573 DOI: 10.3389/fimmu.2024.1431681] [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: 05/12/2024] [Accepted: 07/16/2024] [Indexed: 08/17/2024] Open
Abstract
The two primary types of non-puerperal mastitis (NPM) are granulomatous lobular mastitis (GLM) and plasma cell mastitis (PCM). Existing research indicates that immune inflammatory response is considered to be the core of the pathogenesis of GLM and PCM, and both innate and adaptive immune responses play an important role in the pathophysiology of PCM and GLM. However, the regulatory balance between various immune cells in these diseases is still unclear. Consequently, we present a comprehensive summary of the immune-related variables and recent advances in GLM and PCM.
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Affiliation(s)
- Yao Zhou
- Department of Galactophore, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Jie Gong
- Department of Galactophore, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xianguang Deng
- Department of Galactophore, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Lele Shen
- Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Lifang Liu
- Department of Galactophore, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
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12
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Wang Y, Mang X, Guo X, Pu J. Distinct cuproptosis patterns in hepatocellular carcinoma patients correlate with unique immune microenvironment characteristics and cell-cell communication, contributing to varied overall survival outcomes. Front Immunol 2024; 15:1379690. [PMID: 38868777 PMCID: PMC11168106 DOI: 10.3389/fimmu.2024.1379690] [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: 01/31/2024] [Accepted: 05/01/2024] [Indexed: 06/14/2024] Open
Abstract
Background Hepatocellular carcinoma (HCC), a prevalent cancer, is linked to cuproptosis in tumor progression. However, cuproptosis's impact on HCC prognosis and its role in the tumor microenvironment remain unclear. We aimed to explore the correlation between cellular cuproptosis and the immune microenvironment in HCC, providing potential immunotherapeutic insights. Methods Examining cuproptosis-related genes and the immune microenvironment through consensus clustering and WGCNA. Risk models were constructed using LASSO Cox analysis and validated in an independent cohort. Gene expression data from The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database were utilized. We scored cuproptosis expression and explored immunoinfiltration and cell-cell communication. Differential signals in T_memory cells were compared across different cuproptosis levels. Results Cuproptosis genes associated with fibroblast recruitment (GLS) and macrophage infiltration (FDX1). Liver cancer patients categorized into two subtypes based on cuproptosis gene expression. High expression of DLAT, GLS, and CDKN2A linked to immunosuppression (TGF-β), while high FDX1, MTF1, LIAS, and LIPT1 expression enhanced communication with non-immune cells. Developed reliable prognostic signature score and nomogram using cuproptosis-related genes. Single-cell analysis revealed differences in T_memory and TAM infiltration based on cuproptosis scores, with SPP1 and MIF as dominant signaling molecules. Finally, the results of in vitro experiments showed that when DLAT or CDKN2A was knocked down, the proliferation, migration, and invasion of HCC cells were significantly decreased. Conclusion Our study demonstrates that cuproptosis affects the immune microenvironment and cell-cell communication. Identified 9 genetic markers predicting survival outcomes and immunotherapy responses. Evaluating cuproptosis signaling can optimize immunotherapeutic strategies for hepatocellular carcinoma.
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Affiliation(s)
- Yanhong Wang
- Shanghai Fourth People’s Hospital, and School of Medicine, Tongji University, Shanghai, China
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- Department of Pharmacy, People's Hospital of Gansu Province, Lanzhou, Gansu, China
| | - Xinyu Mang
- Department of Biochemistry and Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Xiaohong Guo
- Department of Pharmacy, People's Hospital of Gansu Province, Lanzhou, Gansu, China
| | - Junfeng Pu
- Department of Pharmacy, People's Hospital of Gansu Province, Lanzhou, Gansu, China
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13
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Holbrook BC, Clemens EA, Alexander-Miller MA. Sex-Dependent Effects on Influenza-Specific Antibody Quantity and Neutralizing Activity following Vaccination of Newborn Non-Human Primates Is Determined by Adjuvants. Vaccines (Basel) 2024; 12:415. [PMID: 38675797 PMCID: PMC11054256 DOI: 10.3390/vaccines12040415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
A number of studies have demonstrated the role of sex in regulating immune responses to vaccination. However, these findings have been limited to adults for both human and animal models. As a result, our understanding of the impact of sex on vaccine responses in the newborn is highly limited. Here, we probe this important question using a newborn non-human primate model. We leveraged our prior analysis of two cohorts of newborns, with one being mother-reared and one nursery-reared. This provided adequate numbers of males and females to interrogate the impact of sex on the response to inactivated influenza vaccines alone or adjuvanted with R848, flagellin, or both. We found that, in contrast to what has been reported in adults, the non-adjuvanted inactivated influenza virus vaccine induced similar levels of virus-specific IgG in male and female newborns. However, the inclusion of R848, either alone or in combination with flagellin, resulted in higher antibody titers in females compared to males. Sex-specific increases in the neutralizing antibody were only observed when both R848 and flagellin were present. These data, generated in the highly translational NHP newborn model, provide novel insights into the role of sex in the immune response of newborns.
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Affiliation(s)
| | | | - Martha A. Alexander-Miller
- Department of Microbiology and Immunology, Wake Forest University School of Medicine, Rm 2E-018 Biotech Place, 575 North Patterson Ave., Winston-Salem, NC 27101, USA; (B.C.H.); elene.a.- (E.A.C.)
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14
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Carroll SL, Pasare C, Barton GM. Control of adaptive immunity by pattern recognition receptors. Immunity 2024; 57:632-648. [PMID: 38599163 PMCID: PMC11037560 DOI: 10.1016/j.immuni.2024.03.014] [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: 01/20/2024] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 04/12/2024]
Abstract
One of the most significant conceptual advances in immunology in recent history is the recognition that signals from the innate immune system are required for induction of adaptive immune responses. Two breakthroughs were critical in establishing this paradigm: the identification of dendritic cells (DCs) as the cellular link between innate and adaptive immunity and the discovery of pattern recognition receptors (PRRs) as a molecular link that controls innate immune activation as well as DC function. Here, we recount the key events leading to these discoveries and discuss our current understanding of how PRRs shape adaptive immune responses, both indirectly through control of DC function and directly through control of lymphocyte function. In this context, we provide a conceptual framework for how variation in the signals generated by PRR activation, in DCs or other cell types, can influence T cell differentiation and shape the ensuing adaptive immune response.
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Affiliation(s)
- Shaina L Carroll
- Division of Immunology & Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA
| | - Chandrashekhar Pasare
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH USA
| | - Gregory M Barton
- Division of Immunology & Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720 USA.
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15
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Si F, Liu X, Tao Y, Zhang Y, Ma F, Hsueh EC, Puram SV, Peng G. Blocking senescence and tolerogenic function of dendritic cells induced by γδ Treg cells enhances tumor-specific immunity for cancer immunotherapy. J Immunother Cancer 2024; 12:e008219. [PMID: 38580332 PMCID: PMC11002396 DOI: 10.1136/jitc-2023-008219] [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: 02/23/2024] [Indexed: 04/07/2024] Open
Abstract
BACKGROUND Regulatory T (Treg) cells are a key component in maintaining the suppressive tumor microenvironment and immune suppression in different types of cancers. A precise understanding of the molecular mechanisms used by Treg cells for immune suppression is critical for the development of effective strategies for cancer immunotherapy. METHODS Senescence development and tolerogenic functions of dendritic cells (DCs) induced by breast cancer tumor-derived γδ Treg cells were fully characterized using real-time PCR, flow cytometry, western blot, and functional assays. Loss-of-function strategies with pharmacological inhibitor and/or neutralizing antibody were used to identify the potential molecule(s) and pathway(s) involved in DC senescence and dysfunction induced by Treg cells. Impaired tumor antigen HER2-specific recognition and immune response of senescent DCs induced by γδ Treg cells were explored in vitro and in vivo in humanized mouse models. In addition, the DC-based HER2 tumor vaccine immunotherapy in breast cancer models was performed to explore the enhanced antitumor immunity via prevention of DC senescence through blockages of STAT3 and programmed death-ligand 1 (PD-L1) signaling. RESULTS We showed that tumor-derived γδ Treg cells promote the development of senescence in DCs with tolerogenic functions in breast cancer. Senescent DCs induced by γδ Treg cells suppress Th1 and Th17 cell differentiation but promote the development of Treg cells. In addition, we demonstrated that PD-L1 and STAT3 signaling pathways are critical and involved in senescence induction in DCs mediated by tumor-derived γδ Treg cells. Importantly, our complementary in vivo studies further demonstrated that blockages of PD-L1 and/or STAT3 signaling can prevent γδ Treg-induced senescence and reverse tolerogenic functions in DCs, resulting in enhanced HER2 tumor-specific immune responses and immunotherapy efficacy in human breast cancer models. CONCLUSIONS These studies not only dissect the suppressive mechanism mediated by tumor-derived γδ Treg cells on DCs in the tumor microenvironment but also provide novel strategies to prevent senescence and dysfunction in DCs and enhance antitumor efficacy mediated by tumor-specific T cells for cancer immunotherapy.
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Affiliation(s)
- Fusheng Si
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri, USA
| | - Xia Liu
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA
| | - Yan Tao
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA
| | - Yuanqin Zhang
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA
| | - Feiya Ma
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri, USA
| | - Eddy C Hsueh
- Division of General Surgery and Department of Surgery, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Sidharth V Puram
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Guangyong Peng
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri, USA
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
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16
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Hu A, Sun L, Lin H, Liao Y, Yang H, Mao Y. Harnessing innate immune pathways for therapeutic advancement in cancer. Signal Transduct Target Ther 2024; 9:68. [PMID: 38523155 PMCID: PMC10961329 DOI: 10.1038/s41392-024-01765-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/18/2024] [Accepted: 02/03/2024] [Indexed: 03/26/2024] Open
Abstract
The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.
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Affiliation(s)
- Ankang Hu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
- Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Li Sun
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Hao Lin
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Yuheng Liao
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, P.R. China
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China.
- Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
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17
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Reghu G, Vemula PK, Bhat SG, Narayanan S. Harnessing the innate immune system by revolutionizing macrophage-mediated cancer immunotherapy. J Biosci 2024; 49:63. [PMID: 38864238 PMCID: PMC11286319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/18/2024] [Accepted: 02/03/2024] [Indexed: 06/13/2024]
Abstract
Immunotherapy is a promising and safer alternative to conventional cancer therapies. It involves adaptive T-cell therapy, cancer vaccines, monoclonal antibodies, immune checkpoint blockade (ICB), and chimeric antigen receptor (CAR) based therapies. However, most of these modalities encounter restrictions in solid tumours owing to a dense, highly hypoxic and immune-suppressive microenvironment as well as the heterogeneity of tumour antigens. The elevated intra-tumoural pressure and mutational rates within fastgrowing solid tumours present challenges in efficient drug targeting and delivery. The tumour microenvironment is a dynamic niche infiltrated by a variety of immune cells, most of which are macrophages. Since they form a part of the innate immune system, targeting macrophages has become a plausible immunotherapeutic approach. In this review, we discuss several versatile approaches (both at pre-clinical and clinical stages) such as the direct killing of tumour-associated macrophages, reprogramming pro-tumour macrophages to anti-tumour phenotypes, inhibition of macrophage recruitment into the tumour microenvironment, novel CAR macrophages, and genetically engineered macrophages that have been devised thus far. These strategies comprise a strong and adaptable macrophage-toolkit in the ongoing fight against cancer and by understanding their significance, we may unlock the full potential of these immune cells in cancer therapy.
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Affiliation(s)
- Gayatri Reghu
- Department of Biotechnology, Cochin University of Science and Technology, Kochi 682 022, India
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Yang Y, Jin C, Yeo A, Jin B. Multiple Factors Determine the Oncolytic or Carcinogenic Effects of TLRs Activation in Cancer. J Immunol Res 2024; 2024. [DOI: 10.1155/2024/1111551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 12/13/2023] [Indexed: 01/05/2025] Open
Abstract
Toll‐like receptors (TLRs) belong to a germline‐encoded protein family. These are pattern recognition receptors. They sense pathogen‐associated molecular patterns (PAMPs). When this occurs, activation of the NF‐ĸB pathway follows. This triggers the innate immune response of the host. The consequent inflammatory cytokine response usually contributes to the elimination of the pathogen. Activation of TLRs also induces an adaptive immune response by a cross‐prime mechanism. This mechanism is employed in cancer immunotherapy. Using TLR ligands as adjuvants induces upregulation of costimulatory signals which in turn activates a cytotoxic leukocyte response against cancer cells. However, TLRs are also overexpressed in human cancer cells resulting in increased cell proliferation, migration, invasion, and angiogenesis. An intracellular adaptor, myeloid differentiation factor 88 (MyD88) probably mediates this process. MyD88 is intimately involved with all TLRs except TLR3. One consequence of the interaction between a TLR and MyD88 is activation of NF‐ĸB. In this context of a variety of proinflammtory cytokines being produced, chronic inflammation may result. Inflammation is an important protective mechanism. However, chronic inflammation is also involved in carcinogenesis. Activation of NF‐ĸB inhibits apoptosis and under certain circumstances, tumor cell survival. In this review, the potential therapeutic value of TLRs in immunotherapy and its role in oncogenesis are explored. The emerging use of artificial intelligence is mentioned.
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Malik JA, Kaur G, Agrewala JN. Revolutionizing medicine with toll-like receptors: A path to strengthening cellular immunity. Int J Biol Macromol 2023; 253:127252. [PMID: 37802429 DOI: 10.1016/j.ijbiomac.2023.127252] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 10/01/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
Toll-like receptors play a vital role in cell-mediated immunity, which is crucial for the immune system's defense against pathogens and maintenance of homeostasis. The interaction between toll-like-receptor response and cell-mediated immunity is complex and essential for effectively eliminating pathogens and maintaining immune surveillance. In addition to pathogen recognition, toll-like receptors serve as adjuvants in vaccines, as molecular sensors, and recognize specific patterns associated with pathogens and danger signals. Incorporating toll-like receptor ligands into vaccines can enhance the immune response to antigens, making them potent adjuvants. Furthermore, they bridge the innate and adaptive immune systems and improve antigen-presenting cells' capacity to process and present antigens to T cells. The intricate signaling pathways and cross-talk between toll-like-receptor and T cell receptor (TCR) signaling emphasize their pivotal role in orchestrating effective immune responses against pathogens, thus facilitating the development of innovative vaccine strategies. This article provides an overview of the current understanding of toll-like receptor response and explores their potential clinical applications. By unraveling the complex mechanisms of toll-like-receptor signaling, we can gain novel insights into immune responses and potentially develop innovative therapeutic approaches. Ongoing investigations into the toll-like-receptor response hold promise in the future in enhancing our ability to combat infections, design effective vaccines, and improve clinical outcomes.
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Affiliation(s)
- Jonaid Ahmad Malik
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology, Ropar, Punjab 140001, India
| | - Gurpreet Kaur
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology, Ropar, Punjab 140001, India; Department of Biotechnology, Chandigarh Group of Colleges, Landran, Mohali, Punjab 140055, India
| | - Javed N Agrewala
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology, Ropar, Punjab 140001, India.
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Temchura V, Wagner JT, Damm D. Immunogenicity of Recombinant Lipid-Based Nanoparticle Vaccines: Danger Signal vs. Helping Hand. Pharmaceutics 2023; 16:24. [PMID: 38258035 PMCID: PMC10818441 DOI: 10.3390/pharmaceutics16010024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 01/24/2024] Open
Abstract
Infectious diseases are a predominant problem in human health. While the incidence of many pathogenic infections is controlled by vaccines, some pathogens still pose a challenging task for vaccine researchers. In order to face these challenges, the field of vaccine development has changed tremendously over the last few years. For non-replicating recombinant antigens, novel vaccine delivery systems that attempt to increase the immunogenicity by mimicking structural properties of pathogens are already approved for clinical applications. Lipid-based nanoparticles (LbNPs) of different natures are vesicles made of lipid layers with aqueous cavities, which may carry antigens and other biomolecules either displayed on the surface or encapsulated in the cavity. However, the efficacy profile of recombinant LbNP vaccines is not as high as that of live-attenuated ones. This review gives a compendious picture of two approaches that affect the immunogenicity of recombinant LbNP vaccines: (i) the incorporation of immunostimulatory agents and (ii) the utilization of pre-existing or promiscuous cellular immunity, which might be beneficial for the development of tailored prophylactic and therapeutic LbNP vaccine candidates.
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Affiliation(s)
- Vladimir Temchura
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | | | - Dominik Damm
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany;
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Fang YD, Liu JY, Xie F, Liu LP, Zeng WW, Wang WH. Antibody preparation and age-dependent distribution of TLR8 in Bactrian camel spleens. BMC Vet Res 2023; 19:276. [PMID: 38104080 PMCID: PMC10725000 DOI: 10.1186/s12917-023-03812-z] [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: 05/19/2023] [Accepted: 11/10/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND Toll-like receptor 8 (TLR8) can recognize specific pathogen-associated molecular patterns and exert multiple immunological functions through activation of signaling cascades. However, the precise distribution and age-related alterations of TLR8 in the spleens of Bactrian camels have not yet been investigated. This study aimed to prepare a rabbit anti-Bactrian camel TLR8 polyclonal antibody and elucidate the distribution of TLR8 in the spleens of Bactrian camels at different age groups. The methodology involved the construction of the pET-28a-TLR8 recombinant plasmid, followed by the expression of TLR8 recombinant protein via prokaryotic expression. Subsequently, rabbits were immunized with the purified protein to prepare the TLR8 polyclonal antibody. Finally, twelve Alashan Bactrian camels were categorized into four groups: young (1-2 years), pubertal (3-5 years), middle-aged (6-16 years) and old (17-20 years). These camels received intravenous sodium pentobarbital (20 mg/kg) anesthesia and were exsanguinated to collect spleen samples. Immunohistochemical techniques were employed to observe and analyze the distribution patterns and age-related changes of TLR8 in the spleen. RESULTS The results showed that the TLR8 recombinant protein was expressed in the form of inclusion body with a molecular weight of 52 kDa, and the optimal induction condition involved 0.3 mmol/L IPTG induction for 8 h. The prepared antibody yielded a titer of 1:32 000, and the antibody demonstrated specific binding to TLR8 recombinant protein. TLR8 positive cells exhibited a consistent distribution pattern in the spleen across different age groups of Bactrian camels, primarily scattered within the periarterial lymphatic sheath of the white pulp, marginal zone, and red pulp. The predominant cell type expressing TLR8 was macrophages, with expression also observed in neutrophils and dendritic cells. Statistical analysis revealed that there were significant differences in the distribution density of TLR8 positive cells among different spleen regions at the same age, with the red pulp, marginal zone, and white pulp showing a descending order (P<0.05). Age-related changes indicated that the distribution density in the marginal zone and red pulp exhibited a similar trend of initially increasing and subsequently decreasing from young to old camels. As camels age, there was a significant decrease in the distribution density across all spleen regions (P<0.05). CONCLUSIONS The results confirmed that this study successfully prepared a rabbit anti-Bactrian camel TLR8 polyclonal antibody with good specificity. TLR8 positive cells were predominantly located in the red pulp and marginal zone of the spleen, signifying their pivotal role in the innate immune response of the spleen. Aging was found to significantly reduce the density of TLR8 positive cells, while leaving their scattered distribution characteristics unaffected. These findings provide valuable support for further investigations into the immunomorphology and immunosenescence of the spleen in Bactrian camels.
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Affiliation(s)
- Ying-Dong Fang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Jing-Yu Liu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Fei Xie
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Li-Ping Liu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Wei-Wei Zeng
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China
| | - Wen-Hui Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, 730070, China.
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22
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Zhang X, Zhang K, Yan L, Wang P, Zhao F, Hu S. The role of toll-like receptors in immune tolerance induced by Helicobacter pylori infection. Helicobacter 2023; 28:e13020. [PMID: 37691007 DOI: 10.1111/hel.13020] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/11/2023] [Accepted: 08/29/2023] [Indexed: 09/12/2023]
Abstract
Helicobacter pylori (H. pylori) is a gram-negative, microaerobic bacterium that colonizes the gastric mucosa in about half of the world's population. H. pylori infection can lead to various diseases. Chronic infection by H. pylori exposes the gastric mucosa to bacterial components such as lipopolysaccharide (LPS), outer membrane vesicles (OMVs), and several toxic proteins. Infected with H. pylori activates the release of pro-inflammatory factors and triggers inflammatory responses that damage the gastric mucosa. As the only microorganism that permanently colonizes the human stomach, H. pylori can suppress host immunity to achieve long-term colonization. Toll-like receptors (TLRs) play a crucial role in T-cell activation, promoting innate immune responses and immune tolerance during H. pylori infection. Among the 10 TLRs found in humans, TLR2, TLR4, TLR5, and TLR9 have been thoroughly investigated in relation to H. pylori-linked immune regulation. In the present review, we provide a comprehensive analysis of the various mechanisms employed by different TLRs in the induction of immune tolerance upon H. pylori infection, which will contribute to the research of pathogenic mechanism of H. pylori.
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Affiliation(s)
- Xiulin Zhang
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Ke Zhang
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Linlin Yan
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Pengfei Wang
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Fan Zhao
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
| | - Shoukui Hu
- Department of Clinical Laboratory, Peking University Shougang Hospital, Beijing, China
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23
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Chen H, Zhang Y, Chen X, Xu R, Zhu Y, He D, Cheng Y, Wang Z, Qing X, Cao K. Hypoxia is correlated with the tumor immune microenvironment: Potential application of immunotherapy in bladder cancer. Cancer Med 2023; 12:22333-22353. [PMID: 38063246 PMCID: PMC10757107 DOI: 10.1002/cam4.6617] [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: 04/06/2022] [Revised: 10/16/2022] [Accepted: 11/17/2022] [Indexed: 12/31/2023] Open
Abstract
OBJECTIVE Hypoxia, which can considerably affect the tumor microenvironment, hinders the use of immunotherapy in bladder cancer (BLCA). Therefore, we aimed to identify reliable hypoxia-related biomarkers to guide clinical immunotherapy in BLCA. METHODS Using data downloaded from TCGA-BLCA cohort, we determined BLCA subtypes which divide 408 samples into different subtypes. Tumor immune infiltration levels of two clusters were quantified using ssGSEA, MCPcounter, EPIC, ESTIMATE, and TIMER algorithms. Next, we constructed a hypoxia score based on the expression of hypoxia-related genes. The IMvigor210 cohort and SubMap analysis were used to predict immunotherapeutic responses in patients with different hypoxia scores. Hub genes were screened using cytoscape, immunohistochemistry (IHC), and multispectral immunofluorescence were used to detect the spatial distribution of immune markers. RESULTS Patients with BLCA were categorized into cluster1 (n = 227) and Cluster2 (n = 181). Immune infiltration and expression of immune markers were higher in Cluster1. Immune infiltration was also more obvious in the high-hypoxia score group which related to a better predicted response to immunotherapy. IHC, and multispectral immunofluorescence confirmed the importance of TLR8 in immune infiltration and immune phenotype. CONCLUSIONS BLCA subtype can evaluate the infiltration of immune cells in the tumor microenvironment of different patients. Hypoxia score in this study could effectively predict immunotherapeutic responses in patients with BLCA. TLR8 may be a potential target for clinical immunotherapy.
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Affiliation(s)
- Haotian Chen
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Yao Zhang
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Xingyu Chen
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Runshi Xu
- Department of Pathology, Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Yuxing Zhu
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Dong He
- Department of Respiration, The Second People's Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, China
| | - YaXin Cheng
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhanwang Wang
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiang Qing
- Department of Otolaryngology-Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Ke Cao
- Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China
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24
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Wan T, Wang Y, He K, Zhu S. Microbial sensing in the intestine. Protein Cell 2023; 14:824-860. [PMID: 37191444 PMCID: PMC10636641 DOI: 10.1093/procel/pwad028] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/04/2023] [Indexed: 05/17/2023] Open
Abstract
The gut microbiota plays a key role in host health and disease, particularly through their interactions with the immune system. Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota, which is influenced by the highly co-evolved immune-microbiota interactions. The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system. In this review, we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes. We further highlight the essential roles of pattern recognition receptors (PRRs), the G protein-coupled receptors (GPCRs), aryl hydrocarbon receptor (AHR) and the nuclear receptors expressed in the intestinal epithelial cells (IECs) and the intestine-resident immune cells. We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease (IBD).
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Affiliation(s)
- Tingting Wan
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Yalong Wang
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Kaixin He
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Shu Zhu
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
- Department of Digestive Disease, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China
- Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China
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25
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Xiao Y, Schroeter A, Martin F, Matsunaga T, Nakamori K, Roesel MJ, Habal M, Chong AS, Zhou H, Tullius SG. Sex as a biological variable: Mechanistic insights and clinical relevance in solid organ transplantation. Am J Transplant 2023; 23:1661-1672. [PMID: 37543092 PMCID: PMC10838351 DOI: 10.1016/j.ajt.2023.07.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 07/06/2023] [Accepted: 07/10/2023] [Indexed: 08/07/2023]
Abstract
Biological sex affects immunity broadly, with recognized effects on the incidence and severity of autoimmune diseases, infections, and malignancies. Consequences of sex on alloimmunity and outcomes in solid organ transplantation are less well defined. Clinical studies have shown that donor and recipient sex independently impact transplant outcomes, which are further modified by aging. Potential mechanisms have thus far not been detailed and may include hormonal, genetic, and epigenetic components. Here, we summarize relevant findings in immunity in addition to studies in clinical and experimental organ transplantation detailing the effects of biological sex on alloimmunity. Understanding both clinical impact and mechanisms is expected to provide critical insights on the complexity of alloimmune responses, with the potential to fine-tune treatment and allocation while providing a rationale to include both sexes in transplant research.
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Affiliation(s)
- Yao Xiao
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Andreas Schroeter
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Regenerative Medicine and Experimental Surgery, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Lower Saxony, Germany
| | - Friederike Martin
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Surgery, CVK/CCM, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Tomohisa Matsunaga
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Keita Nakamori
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Maximilian J Roesel
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), Berlin, Germany
| | - Marlena Habal
- Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, Columbia University, New York, New York, USA
| | - Anita S Chong
- Department of Surgery, University of Chicago, Chicago, Illinois, USA
| | - Hao Zhou
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Stefan G Tullius
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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Chakraborty S, Ye J, Wang H, Sun M, Zhang Y, Sang X, Zhuang Z. Application of toll-like receptors (TLRs) and their agonists in cancer vaccines and immunotherapy. Front Immunol 2023; 14:1227833. [PMID: 37936697 PMCID: PMC10626551 DOI: 10.3389/fimmu.2023.1227833] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/10/2023] [Indexed: 11/09/2023] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) expressed in various immune cell types and perform multiple purposes and duties involved in the induction of innate and adaptive immunity. Their capability to propagate immunity makes them attractive targets for the expansion of numerous immunotherapeutic approaches targeting cancer. These immunotherapeutic strategies include using TLR ligands/agonists as monotherapy or combined therapeutic strategies. Several TLR agonists have demonstrated significant efficacy in advanced clinical trials. In recent years, multiple reports established the applicability of TLR agonists as adjuvants to chemotherapeutic drugs, radiation, and immunotherapies, including cancer vaccines. Cancer vaccines are a relatively novel approach in the field of cancer immunotherapy and are currently under extensive evaluation for treating different cancers. In the present review, we tried to deliver an inclusive discussion of the significant TLR agonists and discussed their application and challenges to their incorporation into cancer immunotherapy approaches, particularly highlighting the usage of TLR agonists as functional adjuvants to cancer vaccines. Finally, we present the translational potential of rWTC-MBTA vaccination [irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists Mannan-BAM, TLR ligands, and anti-CD40 agonisticAntibody], an autologous cancer vaccine leveraging membrane-bound Mannan-BAM, and the immune-inducing prowess of TLR agonists as a probable immunotherapy in multiple cancer types.
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Affiliation(s)
- Samik Chakraborty
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
- NE1 Inc., New York, NY, United States
| | - Juan Ye
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Herui Wang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Mitchell Sun
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Yaping Zhang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Xueyu Sang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Zhengping Zhuang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
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Youness A, Cenac C, Faz-López B, Grunenwald S, Barrat FJ, Chaumeil J, Mejía JE, Guéry JC. TLR8 escapes X chromosome inactivation in human monocytes and CD4 + T cells. Biol Sex Differ 2023; 14:60. [PMID: 37723501 PMCID: PMC10506212 DOI: 10.1186/s13293-023-00544-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 09/04/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored. METHOD In the current study, we used RNA fluorescence in situ hybridization (RNA FISH) to directly visualize, on a single-cell basis, primary transcripts of TLR7 and TLR8 relative to X chromosome territories in CD14+ monocytes and CD4+ T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry. RESULTS Using RNA FISH, we show that TLR8, like TLR7, evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells. CONCLUSIONS TLR8, mirroring TLR7, escapes XCI in human monocytes and CD4+ T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases.
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Affiliation(s)
- Ali Youness
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (INFINITY), UMR 1291 INSERM, CNRS, Hôpital Purpan, Université de Toulouse, 31024, Toulouse, France
| | - Claire Cenac
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (INFINITY), UMR 1291 INSERM, CNRS, Hôpital Purpan, Université de Toulouse, 31024, Toulouse, France
| | - Berenice Faz-López
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (INFINITY), UMR 1291 INSERM, CNRS, Hôpital Purpan, Université de Toulouse, 31024, Toulouse, France
| | - Solange Grunenwald
- Service d'Endocrinologie, Maladies Métaboliques et Nutrition, Hôpital Larrey, Centre Hospitalier Universitaire (CHU) de Toulouse, 31059, Toulouse, France
| | - Franck J Barrat
- Hospital for Special Surgery, HSS Research Institute and David Z. Rosensweig Genomics Research Center, New York, NY, 10021, USA
- Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY, 10021, USA
| | - Julie Chaumeil
- INSERM, CNRS, Université Paris Cité, Institut Cochin, 75014, Paris, France
| | - José Enrique Mejía
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (INFINITY), UMR 1291 INSERM, CNRS, Hôpital Purpan, Université de Toulouse, 31024, Toulouse, France.
| | - Jean-Charles Guéry
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (INFINITY), UMR 1291 INSERM, CNRS, Hôpital Purpan, Université de Toulouse, 31024, Toulouse, France.
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Gronke K, Nguyen M, Santamaria N, Schumacher J, Yang Y, Sonnert N, Leopold S, Martin AL, Hallet R, Richter K, Schubert DA, Daniel GM, Dylus D, Forkel M, Vieira SM, Schwinge D, Schramm C, Lassen KG, Piali L, Palm NW, Bieniossek C, Kriegel MA. Human Th17- and IgG3-associated autoimmunity induced by a translocating gut pathobiont. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.29.546430. [PMID: 37425769 PMCID: PMC10327010 DOI: 10.1101/2023.06.29.546430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Extraintestinal autoimmune diseases are multifactorial with translocating gut pathobionts implicated as instigators and perpetuators in mice. However, the microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. We show here that the translocating pathobiont Enterococcus gallinarum induces human IFNγ + Th17 differentiation and IgG3 subclass switch of anti- E. gallinarum RNA and correlating anti-human RNA autoantibody responses in patients with systemic lupus erythematosus and autoimmune hepatitis. Human Th17 induction by E. gallinarum is cell-contact dependent and involves TLR8-mediated human monocyte activation. In murine gnotobiotic lupus models, E. gallinarum translocation triggers IgG3 anti-RNA autoantibody titers that correlate with renal autoimmune pathophysiology and with disease activity in patients. Overall, we define cellular mechanisms of how a translocating pathobiont induces human T- and B-cell-dependent autoimmune responses, providing a framework for developing host- and microbiota-derived biomarkers and targeted therapies in extraintestinal autoimmune diseases. One Sentence Summary Translocating pathobiont Enterococcus gallinarum promotes human Th17 and IgG3 autoantibody responses linked to disease activity in autoimmune patients.
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29
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Feng ML, Sun MJ, Xu BY, Liu MY, Zhang HJ, Wu C. Mechanism of ELL-associated factor 2 and vasohibin 1 regulating invasion, migration, and angiogenesis in colorectal cancer. World J Gastroenterol 2023; 29:3770-3792. [PMID: 37426316 PMCID: PMC10324531 DOI: 10.3748/wjg.v29.i24.3770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/08/2023] [Accepted: 05/12/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1 (VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colorectal cancer (CRC). Knockdown of VASH1 enhanced transforming growth factor-β1 (TGF-β1)/Smad3 pathway activity and type I/III collagen production. Our previous findings suggest that ELL-associated factor 2 (EAF2) may play a tumor suppressor and protective role in the development and progression of CRC by regulating signal transducer and activator of transcription 3 (STAT3)/TGF-β1 signaling pathway. However, the functional role and mechanism of VASH1-mediated TGF-β1 related pathway in CRC has not been elucidated.
AIM To investigate the expression of VASH1 in CRC and its correlation with the expression of EAF2. Furthermore, we studied the functional role and mechanism of VASH1 involved in the regulation and protection of EAF2 in CRC cells in vitro.
METHODS We collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein and VASH1 protein in patients with advanced CRC. Following, we investigated the effect and mechanism of EAF2 and VASH1 on the invasion, migration and angiogenesis of CRC cells in vitro using plasmid transfection.
RESULTS Our findings indicated that EAF2 was down-regulated and VASH1 was up-regulated in advanced CRC tissue compared to normal colorectal tissue. Kaplan-Meier survival analysis showed that the higher EAF2 Level group and the lower VASH1 Level group had a higher survival rate. Overexpression of EAF2 might inhibit the activity of STAT3/TGF-β1 pathway by up-regulating the expression of VASH1, and then weaken the invasion, migration and angiogenesis of CRC cells.
CONCLUSION This study suggests that EAF2 and VASH1 may serve as new diagnostic and prognostic markers for CRC, and provide a clinical basis for exploring new biomarkers for CRC. This study complements the mechanism of EAF2 in CRC cells, enriches the role and mechanism of CRC cell-derived VASH1, and provides a new possible subtype of CRC as a therapeutic target of STAT3/TGF-β1 pathway.
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Affiliation(s)
- Ming-Liang Feng
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ming-Jun Sun
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bo-Yang Xu
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Meng-Yuan Liu
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hui-Jing Zhang
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Can Wu
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
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30
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Xia M, Blazevic A, Fiore-Gartland A, Hoft DF. Impact of BCG vaccination on the repertoire of human γδ T cell receptors. Front Immunol 2023; 14:1100490. [PMID: 37056780 PMCID: PMC10089282 DOI: 10.3389/fimmu.2023.1100490] [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: 11/16/2022] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
Introduction Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection is a serious threat to human health. Vaccination with BCG prevents the development of the most severe forms of TB disease in infants and was recently shown to prevent Mtb infection in previously uninfected adolescents. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. However, our understanding of the effects of BCG vaccination on γδ T cell responses is incomplete. Methods In this study we performed γδ T cell receptor (TCR) repertoire sequencing of samples provided pre- and post-BCG vaccination from 10 individuals to identify specific receptors and TCR clones that are induced by BCG. Results Overall, there was no change in the diversity of γTCR or δTCR clonotypes in post- vs pre-BCG samples. Furthermore, the frequencies of TCR variable and joining region genes were minimally modulated by BCG vaccination at either the γTCR or δTCR loci. However, the γTCR and δTCR repertoires of individuals were highly dynamic; a median of ~1% of γTCR and ~6% of δTCR in the repertoire were found to significantly expand or contract in post- vs pre-BCG comparisons (FDR-q < 0.05). While many of the clonotypes whose frequency changed after BCG vaccination were not shared among multiple individuals in the cohort, several shared (i.e., "public") clonotypes were identified with a consistent increase or decrease in frequency across more than one individual; the degree of sharing of these clonotypes was significantly greater than the minimal sharing that would be expected among γTCR and δTCR repertoires. An in vitro analysis of Mtb antigen-reactive γδ T cells identified clonotypes that were similar or identical to the single-chain γTCRs and δTCRs that changed consistently after BCG vaccination; pairings of γTCRs and δTCRs that increased after BCG vaccination were significantly over-represented among the Mtb-reactive γδ T cells (p = 1.2e-6). Discussion These findings generate hypotheses about specific γδTCR clonotypes that may expand in response to BCG vaccination and may recognize Mtb antigens. Future studies are required to validate and characterize these clonotypes, with an aim to better understand the role of γδ T cells in Mtb immunity.
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Affiliation(s)
- Mei Xia
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Azra Blazevic
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Andrew Fiore-Gartland
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Daniel F. Hoft
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, United States
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States
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Wahyuningtyas R, Wu ML, Chung WB, Chaung HC, Chang KT. Toll-like Receptor-Mediated Immunomodulation of Th1-Type Response Stimulated by Recombinant Antigen of Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2). Viruses 2023; 15:v15030775. [PMID: 36992483 PMCID: PMC10057405 DOI: 10.3390/v15030775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/05/2023] [Accepted: 03/14/2023] [Indexed: 03/22/2023] Open
Abstract
PRRSV infects CD163-positive macrophages and skews their polarization toward an M2 phenotype, followed by T-cell inactivation. In our previous study, we found that recombinant protein A1 antigen derived from PRRSV-2 was a potential vaccine or adjuvant for immunization against PRRSV-2 infection due to its ability to repolarize macrophages into M1 subtype, thereby reducing CD163 expression for viral entry and promoting immunomodulation for Th1-type responses, except for stimulating Toll-like receptor (TLR) activation. The aim of our current study was to evaluate the effects of another two recombinant antigens, A3 (ORF6L5) and A4 (NLNsp10L11), for their ability to trigger innate immune responses including TLR activation. We isolated pulmonary alveolar macrophages (PAMs) from 8- to 12-week-old specific pathogen free (SPF) piglets and stimulated them with PRRSV (0.01 MOI and 0.05 MOI) or antigens. We also investigated the T-cell differentiation by immunological synapse activation of PAMs and CD4+ T-cells in the cocultured system. To confirm the infection of PRRSV in PAMs, we checked the expression of TLR3, 7, 8, and 9. Our results showed that the expression of TLR3, 7, and 9 were significantly upregulated in PAMs by A3 antigen induction, similar to the extent of PRRSV infection. Gene profile results showed that A3 repolarizes macrophages into the M1 subtype potently, in parallel with A1, as indicated by significant upregulation of proinflammatory genes (TNF-α, IL-6, IL-1β and IL-12). Upon immunological synapse activation, A3 potentially differentiated CD4 T cells into Th1 cells, determined by the expression of IL-12 and IFN-γ secretion. On the contrary, antigen A4 promoted regulatory T cell (T-reg) differentiation by significant upregulation of IL-10 expression. Finally, we concluded that the PRRSV-2 recombinant protein A3 provided better protection against PRRSV infection, suggested by its capability to reeducate immunosuppressive M2 macrophages into proinflammatory M1 cells. As M1 macrophages are prone to be functional antigen-presenting cells (APCs), they can call for TLR activation and Th1-type immune response within the immunological synapse.
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Affiliation(s)
- Rika Wahyuningtyas
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
| | - Mei-Li Wu
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Food Science, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
| | - Wen-Bin Chung
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
| | - Hso-Chi Chaung
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Flow Cytometry Center, Precision Instruments Center, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Correspondence: (H.-C.C.); (K.-T.C.)
| | - Ko-Tung Chang
- Research Centre for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Flow Cytometry Center, Precision Instruments Center, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
- Correspondence: (H.-C.C.); (K.-T.C.)
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Tsang TK, Wang C, Tsang NNY, Fang VJ, Perera RAPM, Malik Peiris JS, Leung GM, Cowling BJ, Ip DKM. Impact of host genetic polymorphisms on response to inactivated influenza vaccine in children. NPJ Vaccines 2023; 8:21. [PMID: 36804941 PMCID: PMC9940051 DOI: 10.1038/s41541-023-00621-1] [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: 10/10/2022] [Accepted: 02/02/2023] [Indexed: 02/22/2023] Open
Abstract
In randomized controlled trials of influenza vaccination, 550 children received trivalent-inactivated influenza vaccine, permitting us to explore relationship between vaccine response and host single nucleotide polymorphisms (SNPs) in 23 candidate genes with adjustment of multiple testing. For host SNPs in TLR7-1817G/T (rs5741880), genotype GT was associated with lower odds (OR: 0.22, 95% CI: 0.09, 0.53) of have post-vaccination hemagglutination-inhibiting (HAI) titers ≥40, compared with genotype GG and TT combined under the over-dominant model. For host SNPs in TLR8-129G/C (rs3764879), genotype GT was associated with lower odds (OR: 0.47; 95% CI: 0.28, 0.80) of have post vaccination HAI titers ≥40 compared with genotype GG and AA combined under the over-dominant model. Our results could contribute to the development of better vaccines that may offer improved protection to all recipients.
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Affiliation(s)
- Tim K. Tsang
- grid.194645.b0000000121742757WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China ,Laboratory of Data Discovery for Health Limited, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China
| | - Can Wang
- grid.194645.b0000000121742757WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Nicole N. Y. Tsang
- grid.194645.b0000000121742757WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Vicky J. Fang
- grid.194645.b0000000121742757WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Ranawaka A. P. M. Perera
- grid.194645.b0000000121742757WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - J. S. Malik Peiris
- grid.194645.b0000000121742757WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China ,grid.194645.b0000000121742757HKU-Pasteur Research Pole, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Gabriel M. Leung
- grid.194645.b0000000121742757WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China ,Laboratory of Data Discovery for Health Limited, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China
| | - Benjamin J. Cowling
- grid.194645.b0000000121742757WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China ,Laboratory of Data Discovery for Health Limited, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China
| | - Dennis K. M. Ip
- grid.194645.b0000000121742757WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
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Li Q, Pan H, Gao Z, Li W, Zhang L, Zhao J, Fang L, Chu Y, Yuan W, Shi J. High-expression of the innate-immune related gene UNC93B1 predicts inferior outcomes in acute myeloid leukemia. Front Genet 2023; 14:1063227. [PMID: 36741319 PMCID: PMC9891309 DOI: 10.3389/fgene.2023.1063227] [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: 10/06/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy with dismal prognosis. Identification of better biomarkers remained a priority to improve established stratification and guide therapeutic decisions. Therefore, we extracted the RNA sequence data and clinical characteristics of AML from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression database (GTEx) to identify the key factors for prognosis. We found UNC93B1 was highly expressed in AML patients and significantly linked to poor clinical features (p < 0.05). We further validated the high expression of UNC93B1 in another independent AML cohort from GEO datasets (p < 0.001) and performed quantitative PCR of patient samples to confirm the overexpression of UNC93B1 in AML (p < 0.005). Moreover, we discovered high level of UNC93B1 was an independent prognostic factor for poorer outcome both in univariate analysis and multivariate regression (p < 0.001). Then we built a nomogram model based on UNC93B1 expression, age, FAB subtype and cytogenetic risk, the concordance index of which for predicting overall survival was 0.729 (p < 0.001). Time-dependent ROC analysis for predicting survival outcome at different time points by UNC93B1 showed the cumulative 2-year survival rate was 43.7%, and 5-year survival rate was 21.9%. The differentially expressed genes (DEGs) between two groups divided by UNC93B1 expression level were enriched in innate immune signaling and metabolic process pathway. Protein-protein interaction (PPI) network indicated four hub genes (S100A9, CCR1, MRC1 and CD1C) interacted with UNC93B1, three of which were also significantly linked to inferior outcome. Furthermore, we discovered high UNC93B1 tended to be infiltrated by innate immune cells, including Macrophages, Dendritic cells, Neutrophils, Eosinophils, and NK CD56dim cells. We also found UNC93B1 had a significantly positive correlation with CD14, CD68 and almost all Toll-like receptors. Finally, we revealed negatively correlated expression of UNC93B1 and BCL2 in AML and conjectured that high-UNC93B1 monocytic AML is more resistant to venetoclax. And we found high MCL-1 expression compensated for BCL-2 loss, thus, we proposed MCL-1 inhibitor might overcome the resistance of venetoclax in AML. Altogether, our findings demonstrated the utility of UNC93B1 as a powerful poor prognostic predictor and alternative therapeutic target.
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Affiliation(s)
- Qiaoli Li
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Hong Pan
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Zhen Gao
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Weiwang Li
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Lele Zhang
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jingyu Zhao
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Liwei Fang
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yajing Chu
- Center for Stem Cell Medicine and Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Weiping Yuan
- Center for Stem Cell Medicine and Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Jun Shi
- Regenerative Medicine Clinic, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China,*Correspondence: Jun Shi,
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Casili G, Paterniti I, Campolo M, Esposito E, Cuzzocrea S. The Role of Neuro-Inflammation and Innate Immunity in Pathophysiology of Brain and Spinal Cord Tumors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1394:41-49. [PMID: 36587380 DOI: 10.1007/978-3-031-14732-6_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Inflammation and innate immune system play a central role in cancers, including those affecting the central nervous system (CNS). Currently, classification of neoplasms, especially regarding gliomas, is established on molecular mutations in isocitrate dehydrogenase (IDH) genes and the presence of co-deletion 1p/19q. Treatment, in most of brain and spinal cord tumors, is centered on surgery, radiotherapy and pharmacological approaches with chemotherapeutic agents. However, the results of the treatments, after several decades, are not completely satisfactory. Cytokines and angiogenic factors are closely linked to the brain cancer behavior. Moreover, recent studies suggest a link between inflammation and tumorigenesis, underlying the complex nature of this topic, especially the anti- and pro-tumoral activities of inflammation and the two-way interactions between immune and tumor cells. The current understanding of the mechanisms by which CNS cancer cells modulate the immune system, especially how bi-directional communications between immune cells and tumor cells create an immunosuppressed microenvironment, gives important information about the promotion of tumor survival and growth. Here, we have briefly reviewed the current literature on this topic, focusing on the possible role of inflammation and innate immunity involved in the origin and in the development of CNS tumors.
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Affiliation(s)
- Giovanna Casili
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31-98166, Messina, Italy
| | - Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31-98166, Messina, Italy
| | - Michela Campolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31-98166, Messina, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31-98166, Messina, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31-98166, Messina, Italy.
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Tambunlertchai S, Geary SM, Salem AK. Topically Applied Resiquimod versus Imiquimod as a Potential Adjuvant in Melanoma Treatment. Pharmaceutics 2022; 14:pharmaceutics14102076. [PMID: 36297510 PMCID: PMC9611754 DOI: 10.3390/pharmaceutics14102076] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 09/17/2022] [Accepted: 09/18/2022] [Indexed: 01/28/2023] Open
Abstract
Melanoma is the most lethal form of skin cancer and surgery remains the preferred and most effective treatment. Nevertheless, there are cases where surgery is not a viable method and alternative treatments are therefore adopted. One such treatment that has been tested is topical 5% imiquimod (IMQ) cream, which, although showing promise as a treatment for melanoma, has been found to have undesirable off-target effects. Resiquimod (RSQ) is an immunomodulatory molecule that can activate immune responses by binding to Toll-like receptors (TLR) 7 and 8 and may be more effective than IMQ in the context of melanoma treatment. RSQ can cross the stratum corneum (SC) easily without requiring pretreatment of the skin. In a gel formulation, RSQ has been studied as a monotherapy and adjuvant for melanoma treatment in pre-clinical studies and as an adjuvant in clinical settings. Although side effects of RSQ in gel formulation were also reported, they were never severe enough for the treatment to be suspended. In this review, we discuss the potential use of RSQ as an adjuvant for melanoma treatment.
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Chan Wah Hak CML, Rullan A, Patin EC, Pedersen M, Melcher AA, Harrington KJ. Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy. Front Oncol 2022; 12:971959. [PMID: 36106115 PMCID: PMC9465159 DOI: 10.3389/fonc.2022.971959] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Radiotherapy is one of the most effective and frequently used treatments for a wide range of cancers. In addition to its direct anti-cancer cytotoxic effects, ionising radiation can augment the anti-tumour immune response by triggering pro-inflammatory signals, DNA damage-induced immunogenic cell death and innate immune activation. Anti-tumour innate immunity can result from recruitment and stimulation of dendritic cells (DCs) which leads to tumour-specific adaptive T-cell priming and immunostimulatory cell infiltration. Conversely, radiotherapy can also induce immunosuppressive and anti-inflammatory mediators that can confer radioresistance. Targeting the DNA damage response (DDR) concomitantly with radiotherapy is an attractive strategy for overcoming radioresistance, both by enhancing the radiosensitivity of tumour relative to normal tissues, and tipping the scales in favour of an immunostimulatory tumour microenvironment. This two-pronged approach exploits genomic instability to circumvent immune evasion, targeting both hallmarks of cancer. In this review, we describe targetable DDR proteins (PARP (poly[ADP-ribose] polymerase); ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) and Wee1 (Wee1-like protein kinase) and their potential intersections with druggable immunomodulatory signalling pathways, including nucleic acid-sensing mechanisms (Toll-like receptors (TLR); cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and retinoic acid-inducible gene-I (RIG-I)-like receptors), and how these might be exploited to enhance radiation therapy. We summarise current preclinical advances, recent and ongoing clinical trials and the challenges of therapeutic combinations with existing treatments such as immune checkpoint inhibitors.
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Affiliation(s)
| | - Antonio Rullan
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Emmanuel C. Patin
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Malin Pedersen
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Alan A. Melcher
- Translational Immunotherapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Kevin J. Harrington
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
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Martín-Medina A, Cerón-Pisa N, Martinez-Font E, Shafiek H, Obrador-Hevia A, Sauleda J, Iglesias A. TLR/WNT: A Novel Relationship in Immunomodulation of Lung Cancer. Int J Mol Sci 2022; 23:6539. [PMID: 35742983 PMCID: PMC9224119 DOI: 10.3390/ijms23126539] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 02/07/2023] Open
Abstract
The most frequent cause of death by cancer worldwide is lung cancer, and the 5-year survival rate is still very poor for patients with advanced stage. Understanding the crosstalk between the signaling pathways that are involved in disease, especially in metastasis, is crucial to developing new targeted therapies. Toll-like receptors (TLRs) are master regulators of the immune responses, and their dysregulation in lung cancer is linked to immune escape and promotes tumor malignancy by facilitating angiogenesis and proliferation. On the other hand, over-activation of the WNT signaling pathway has been reported in lung cancer and is also associated with tumor metastasis via induction of Epithelial-to-mesenchymal-transition (EMT)-like processes. An interaction between both TLRs and the WNT pathway was discovered recently as it was found that the TLR pathway can be activated by WNT ligands in the tumor microenvironment; however, the implications of such interactions in the context of lung cancer have not been discussed yet. Here, we offer an overview of the interaction of TLR-WNT in the lung and its potential implications and role in the oncogenic process.
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Affiliation(s)
- Aina Martín-Medina
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
| | - Noemi Cerón-Pisa
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
| | - Esther Martinez-Font
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Medical Oncology Department, Hospital Universitario Son Espases, 07120 Palma, Spain
| | - Hanaa Shafiek
- Chest Diseases Department, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt
| | - Antònia Obrador-Hevia
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Molecular Diagnosis Unit, Hospital Universitario Son Espases, 07120 Palma, Spain
| | - Jaume Sauleda
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Department of Respiratory Medicine, Hospital Universitario Son Espases, 07120 Palma, Spain
- Centro de Investigación Biomédica en Red in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| | - Amanda Iglesias
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Centro de Investigación Biomédica en Red in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
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Huang L, Ge X, Liu Y, Li H, Zhang Z. The Role of Toll-like Receptor Agonists and Their Nanomedicines for Tumor Immunotherapy. Pharmaceutics 2022; 14:pharmaceutics14061228. [PMID: 35745800 PMCID: PMC9230510 DOI: 10.3390/pharmaceutics14061228] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/20/2022] [Accepted: 06/07/2022] [Indexed: 01/11/2023] Open
Abstract
Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a critical role in innate and adaptive immunity. Toll-like receptor agonists (TLRa) as vaccine adjuvant candidates have become one of the recent research hotspots in the cancer immunomodulatory field. Nevertheless, numerous current systemic deliveries of TLRa are inappropriate for clinical adoption due to their low efficiency and systemic adverse reactions. TLRa-loaded nanoparticles are capable of ameliorating the risk of immune-related toxicity and of strengthening tumor suppression and eradication. Herein, we first briefly depict the patterns of TLRa, followed by the mechanism of agonists at those targets. Second, we summarize the emerging applications of TLRa-loaded nanomedicines as state-of-the-art strategies to advance cancer immunotherapy. Additionally, we outline perspectives related to the development of nanomedicine-based TLRa combined with other therapeutic modalities for malignancies immunotherapy.
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Affiliation(s)
| | | | | | - Hui Li
- Correspondence: (H.L.); (Z.Z.)
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Targeting toll-like receptors on T cells as a therapeutic strategy against tumors. Int Immunopharmacol 2022; 107:108708. [DOI: 10.1016/j.intimp.2022.108708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/05/2022] [Accepted: 03/13/2022] [Indexed: 12/11/2022]
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Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol 2022. [PMID: 35309296 DOI: 10.3389/fimmu.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
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Affiliation(s)
- Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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Yang R, Yu S, Xu T, Zhang J, Wu S. Emerging role of RNA sensors in tumor microenvironment and immunotherapy. J Hematol Oncol 2022; 15:43. [PMID: 35413927 PMCID: PMC9006576 DOI: 10.1186/s13045-022-01261-z] [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] [Received: 01/09/2022] [Accepted: 04/01/2022] [Indexed: 12/16/2022] Open
Abstract
RNA sensors detect foreign and endogenous RNAs to protect the host by initiating innate and adaptive immune response. In tumor microenvironment (TME), activation of RNA sensors induces tumor-inhibitory cytotoxic T lymphocyte responses and inhibits the activity of immunosuppressive cells though stimulating type I IFN signaling pathway. These characteristics allow RNA sensors to be prospective targets in tumor immunotherapy. Therefore, a comprehensive understanding of the roles of RNA sensors in TME could provide new insight into the antitumor immunotherapy. Moreover, RNA sensors could be prominent triggering targets to synergize with immunotherapies. In this review, we highlight the diverse mechanisms of RNA sensors in cancer immunity and their emerging contributions in cancer immunotherapy, including monotherapy with RNA sensor agonists, as well as combination with chemotherapy, radiotherapy, immune checkpoint blockade or cancer vaccine.
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Affiliation(s)
- Rui Yang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Sihui Yu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Tianhan Xu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jiawen Zhang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China. .,Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Sufang Wu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
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42
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Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol 2022; 13:812774. [PMID: 35309296 PMCID: PMC8927970 DOI: 10.3389/fimmu.2022.812774] [Citation(s) in RCA: 418] [Impact Index Per Article: 139.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/08/2022] [Indexed: 12/13/2022] Open
Abstract
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
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Affiliation(s)
- Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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Fejtkova M, Sukova M, Hlozkova K, Skvarova Kramarzova K, Rackova M, Jakubec D, Bakardjieva M, Bloomfield M, Klocperk A, Parackova Z, Sediva A, Aluri J, Novakova M, Kalina T, Fronkova E, Hrusak O, Malcova H, Sedlacek P, Liba Z, Kudr M, Stary J, Cooper MA, Svaton M, Kanderova V. TLR8/TLR7 dysregulation due to a novel TLR8 mutation causes severe autoimmune hemolytic anemia and autoinflammation in identical twins. Am J Hematol 2022; 97:338-351. [PMID: 34981838 DOI: 10.1002/ajh.26452] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022]
Abstract
Our study presents a novel germline c.1715G>T (p.G572V) mutation in the gene encoding Toll-like receptor 8 (TLR8) causing an autoimmune and autoinflammatory disorder in a family with monozygotic male twins, who suffer from severe autoimmune hemolytic anemia worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis. The pathogenicity of the mutation was confirmed by in vitro assays on transfected cell lines and primary cells. The p.G572V mutation causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to increased pro-inflammatory responses, such as nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This unique TLR8 mutation with partial TLR8 protein loss and hyperinflammatory phenotype mediated by TLR7 ligands represents a novel inborn error of immunity with childhood-onset and a good response to TLR7 inhibition.
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Affiliation(s)
- Martina Fejtkova
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Martina Sukova
- Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Katerina Hlozkova
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Karolina Skvarova Kramarzova
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Marketa Rackova
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - David Jakubec
- Bioinformatics Group, Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic
- Department of Software Engineering, Faculty of Mathematics and Physics Charles University Prague Czech Republic
| | - Marina Bakardjieva
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Marketa Bloomfield
- Department of Paediatrics, First Faculty of Medicine Charles University and Thomayer University Hospital Prague Czech Republic
- Department of Immunology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Adam Klocperk
- Department of Immunology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Zuzana Parackova
- Department of Immunology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Anna Sediva
- Department of Immunology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Jahnavi Aluri
- Division of Rheumatology/Immunology, Department of Pediatrics Washington University School of Medicine St. Louis Missouri USA
| | - Michaela Novakova
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Tomas Kalina
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Eva Fronkova
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Ondrej Hrusak
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Hana Malcova
- Department of Paediatric and Adult Rheumatology University Hospital Motol Prague Czech Republic
| | - Petr Sedlacek
- Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Zuzana Liba
- Department of Paediatric Neurology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Martin Kudr
- Department of Paediatric Neurology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Jan Stary
- Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Megan A. Cooper
- Division of Rheumatology/Immunology, Department of Pediatrics Washington University School of Medicine St. Louis Missouri USA
| | - Michael Svaton
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
| | - Veronika Kanderova
- CLIP ‐ Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic
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Martínez-Espinoza I, Guerrero-Plata A. The Relevance of TLR8 in Viral Infections. Pathogens 2022; 11:134. [PMID: 35215078 PMCID: PMC8877508 DOI: 10.3390/pathogens11020134] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 11/16/2022] Open
Abstract
Toll-like receptors (TLRs) are the largest pattern recognition receptors responsible for activating the innate and adaptive immune response against viruses through the release of inflammatory cytokines and antiviral mediators. Viruses are recognized by several TLRs, including TLR8, which is known to bind ssRNA structures. However, the similarities between TLR8 and TLR7 have obscured the distinctive characteristics of TLR8 activation and its importance in the immune system. Here we discuss the activation and regulation of TLR8 by viruses and its importance in therapeutical options such as vaccine adjuvants and antiviral stimulators.
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Chardin L, Leary A. Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1. Front Oncol 2021; 11:795547. [PMID: 34966689 PMCID: PMC8710491 DOI: 10.3389/fonc.2021.795547] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/22/2021] [Indexed: 12/27/2022] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecologic malignancy, affecting approximately 1 in 70 women with only 45% surviving 5 years after diagnosis. This disease typically presents at an advanced stage, and optimal debulking with platinum-based chemotherapy remains the cornerstone of management. Although most ovarian cancer patients will respond effectively to current management, 70% of them will eventually develop recurrence and novel therapeutic strategies are needed. There is a rationale for immune-oncological treatments (IO) in the managements of patients with OC. Many OC tumors demonstrate tumor infiltrating lymphocytes (TILs) and the degree of TIL infiltration is strongly and reproducibly correlated with survival. Unfortunately, results to date have been disappointing in relapsed OC. Trials have reported very modest single activity with various antibodies targeting PD-1 or PD-L1 resulting in response rate ranging from 4% to 15%. This may be due to the highly immunosuppressive TME of the disease, a low tumor mutational burden and low PD-L1 expression. There is an urgent need to improve our understanding of the immune microenvironment in OC in order to develop effective therapies. This review will discuss immune subpopulations in OC microenvironment, current immunotherapy modalities targeting these immune subsets and data from clinical trials testing IO treatments in OC and its combination with other therapeutic agents.
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Affiliation(s)
- Laure Chardin
- Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, Villejuif, France
| | - Alexandra Leary
- Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, Villejuif, France
- Department of Medical Oncology, Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, Villejuif, France
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Pulukuri AJ, Burt AJ, Opp LK, McDowell CM, Davaritouchaee M, Nielsen AE, Mancini RJ. Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein. Pharmaceuticals (Basel) 2021; 14:ph14121292. [PMID: 34959691 PMCID: PMC8705394 DOI: 10.3390/ph14121292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/04/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
Multidrug-Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux, a process that transports drugs from within a cell to the extracellular space via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR) agonist immunotherapies modulate activity of tumor-infiltrating immune cells in local proximity to cancer cells and could, therefore, benefit from the enhanced drug efflux in MDR cancers. However, the effect of acquired drug resistance on TLR agonist efflux is largely unknown. We begin to address this by investigating P-gp mediated efflux of TLR 7/8 agonists. First, we used functionalized liposomes to determine that imidazoquinoline TLR agonists Imiquimod, Resiquimod, and Gardiquimod are substrates for P-gp. Interestingly, the least potent imidazoquinoline (Imiquimod) was the best P-gp substrate. Next, we compared imidazoquinoline efflux in MDR cancer cell lines with enhanced P-gp expression relative to parent cancer cell lines. Using P-gp competitive substrates and inhibitors, we observed that imidazoquinoline efflux occurs through P-gp and, for Imiquimod, is enhanced as a consequence of acquired drug resistance. This suggests that enhancing efflux susceptibility could be an important consideration in the rational design of next generation immunotherapies that modulate activity of tumor-infiltrating immune cells.
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Affiliation(s)
- Anunay J. Pulukuri
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
| | - Anthony J. Burt
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA 92182, USA
| | - Larissa K. Opp
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
| | - Colin M. McDowell
- School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA;
| | - Maryam Davaritouchaee
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
- Department of Food Science, Cornell University, Ithaca, NY 14853, USA
- The Gene & Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164, USA
| | - Amy E. Nielsen
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
| | - Rock J. Mancini
- Department of Chemistry, Washington State University, Pullman, WA 99164, USA; (A.J.P.); (A.J.B.); (L.K.O.); (M.D.); (A.E.N.)
- The Gene & Linda Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA 99164, USA
- Correspondence:
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Ayithan N, Ghosh A, Dwivedi A, Wallin JJ, Tan SK, Chen D, Kottilil S, Poonia B. Oral Selective TLR8 Agonist Selgantolimod Induces Multiple Immune Cell Responses in Humans. Viruses 2021; 13:v13122400. [PMID: 34960669 PMCID: PMC8706304 DOI: 10.3390/v13122400] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/18/2022] Open
Abstract
TLR8 agonists have the potential for use as immunomodulatory components in therapeutic modalities for viral infections such as chronic HBV (CHB) and HIV. In this study, using peripheral blood samples from a phase 1a clinical trial, we examined the acute effects of a single oral administration of a selective TLR8 agonist on immune cell phenotypes. Administration of the TLR8 agonist selgantolimod (SLGN) in healthy individuals resulted in alteration in frequencies of peripheral blood monocytes, pDCs, mDCs and MAIT cells. Frequencies of mDCs and lymphoid cells significantly reduced after 8 h of SLGN administration, whereas pDC frequencies significantly increased, with changes possibly reflecting migration of different cell types between peripheral and tissue compartments in response to the agonist. Myeloid cell activation was evident by an upregulated expression of co-stimulatory molecules CD40 and CD86 accompanied by the production of IL-6 and IL-18 from these cells. Concomitantly, there was induction of the early activation marker CD69 on innate and adaptive lymphoid cells, including MAIT and NK cell subsets. Further, these activated lymphoid cells had enhanced expression of the effector molecules granzyme B and perforin. Microarray analysis of isolated lymphocytes and monocytes from baseline and post-SLGN treatment revealed changes in expression of genes involved in cellular response to cytokine stimulus, innate immune response, myeloid cell differentiation and antigen receptor-mediated signaling pathway. In a preliminary analysis of samples from CHB patients treated with selgantolimod, activation of innate and adaptive lymphocytes was evident. In conclusion, this first in-human study shows that selgantolimod administration in humans results in activation of multiple immune cell responses with antiviral potential.
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Affiliation(s)
- Natarajan Ayithan
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.A.); (A.G.); (S.K.)
| | - Alip Ghosh
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.A.); (A.G.); (S.K.)
| | - Ankit Dwivedi
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Jeffrey J. Wallin
- Gilead Sciences Inc., Foster City, CA 94404, USA; (J.J.W.); (S.K.T.); (D.C.)
| | - Susanna K. Tan
- Gilead Sciences Inc., Foster City, CA 94404, USA; (J.J.W.); (S.K.T.); (D.C.)
| | - Diana Chen
- Gilead Sciences Inc., Foster City, CA 94404, USA; (J.J.W.); (S.K.T.); (D.C.)
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.A.); (A.G.); (S.K.)
| | - Bhawna Poonia
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.A.); (A.G.); (S.K.)
- Correspondence:
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Xie Y, Xie F, Zhang L, Zhou X, Huang J, Wang F, Jin J, Zhang L, Zeng L, Zhou F. Targeted Anti-Tumor Immunotherapy Using Tumor Infiltrating Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2101672. [PMID: 34658167 PMCID: PMC8596143 DOI: 10.1002/advs.202101672] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/21/2021] [Indexed: 05/08/2023]
Abstract
In the tumor microenvironment, T cells, B cells, and many other cells play important and distinct roles in anti-tumor immunotherapy. Although the immune checkpoint blockade and adoptive cell transfer can elicit durable clinical responses, only a few patients benefit from these therapies. Increased understanding of tumor-infiltrating immune cells can provide novel therapies and drugs that induce a highly specific anti-tumor immune response to certain groups of patients. Herein, the recent research progress on tumor-infiltrating B cells and T cells, including CD8+ T cells, CD4+ T cells, and exhausted T cells and their role in anti-tumor immunity, is summarized. Moreover, several anti-tumor therapy approaches are discussed based on different immune cells and their prospects for future applications in cancer treatment.
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Affiliation(s)
- Yifan Xie
- School of MedicineZhejiang University City CollegeHangzhou310015China
- College of Life SciencesZhejiang UniversityHangzhou310058China
| | - Feng Xie
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
| | - Lei Zhang
- Department of Orthopaedic SurgeryThe Third Affiliated Hospital of Wenzhou Medical UniversityRui'an325200China
| | - Xiaoxue Zhou
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Jun Huang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Fangwei Wang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Jin Jin
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Long Zhang
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Linghui Zeng
- School of MedicineZhejiang University City CollegeHangzhou310015China
| | - Fangfang Zhou
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
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Siu L, Brody J, Gupta S, Marabelle A, Jimeno A, Munster P, Grilley-Olson J, Rook AH, Hollebecque A, Wong RKS, Welsh JW, Wu Y, Morehouse C, Hamid O, Walcott F, Cooper ZA, Kumar R, Ferté C, Hong DS. Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors. J Immunother Cancer 2021; 8:jitc-2020-001095. [PMID: 33037117 PMCID: PMC7549442 DOI: 10.1136/jitc-2020-001095] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2020] [Indexed: 12/22/2022] Open
Abstract
Background MEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors. Patients and methods Eligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response. Results From November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks. Conclusion IT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations. Trial registration number NCT02556463.
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Affiliation(s)
- Lillian Siu
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Joshua Brody
- Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Shilpa Gupta
- Department of Hematology and Oncology, Cleveland Clinic, Cleveland, Ohio, United States
| | | | - Antonio Jimeno
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Denver, Colorado, United States
| | - Pamela Munster
- Department of Medicine (Hematology/Oncology), University of California San Francisco, San Francisco, California, United States
| | - Juneko Grilley-Olson
- Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
| | - Alain H Rook
- Department of Dematology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | | | - Rebecca K S Wong
- Radiation Medicine Program, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
| | - James W Welsh
- Division of Radiation Oncology, Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Yuling Wu
- AstraZeneca, Gaithersburg, Maryland, USA
| | | | - Oday Hamid
- AstraZeneca, Gaithersburg, Maryland, USA
| | | | | | | | | | - David S Hong
- Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Gane EJ, Kim HJ, Visvanathan K, Kim YJ, Nguyen AH, Wallin JJ, Chen DY, McDonald C, Arora P, Tan SK, Gaggar A, Roberts SK, Lim YS. Safety, Pharmacokinetics, and Pharmacodynamics of the Oral TLR8 Agonist Selgantolimod in Chronic Hepatitis B. Hepatology 2021; 74:1737-1749. [PMID: 33704806 DOI: 10.1002/hep.31795] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/04/2021] [Accepted: 02/22/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment. APPROACH AND RESULTS In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, which are important for the expansion and activity of multiple T- cell subsets and innate immunity. CONCLUSION Selgantolimod was safe and well-tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.
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Affiliation(s)
- Edward J Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | | | - Kumar Visvanathan
- St. Vincent's Hospital Melbourne and University of Melbourne, Fitzroy, VIC, Australia
| | - Yoon Jun Kim
- Seoul National University Hospital, Seoul, South Korea
| | | | | | | | | | | | | | | | - Stuart K Roberts
- Alfred Hospital and Monash University, Melbourne, VIC, Australia
| | - Young-Suk Lim
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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