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Immunity Dec 2023In triple-negative breast cancer (TNBC), stromal restriction of CD8 T cells associates with poor clinical outcomes and lack of responsiveness to immune-checkpoint...
In triple-negative breast cancer (TNBC), stromal restriction of CD8 T cells associates with poor clinical outcomes and lack of responsiveness to immune-checkpoint blockade (ICB). To identify mediators of T cell stromal restriction, we profiled murine breast tumors lacking the transcription factor Stat3, which is commonly hyperactive in breast cancers and promotes an immunosuppressive tumor microenvironment. Expression of the cytokine Chi3l1 was decreased in Stat3 tumors. CHI3L1 expression was elevated in human TNBCs and other solid tumors exhibiting T cell stromal restriction. Chi3l1 ablation in the polyoma virus middle T (PyMT) breast cancer model generated an anti-tumor immune response and delayed mammary tumor onset. These effects were associated with increased T cell tumor infiltration and improved response to ICB. Mechanistically, Chi3l1 promoted neutrophil recruitment and neutrophil extracellular trap formation, which blocked T cell infiltration. Our findings provide insight into the mechanism underlying stromal restriction of CD8 T cells and suggest that targeting Chi3l1 may promote anti-tumor immunity in various tumor types.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cytokines; Extracellular Traps; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 38039967
DOI: 10.1016/j.immuni.2023.11.002 -
Viruses Oct 2023JC polyomavirus (JCPyV) is a human-specific polyomavirus that establishes a silent lifelong infection in multiple peripheral organs, predominantly those of the urinary... (Review)
Review
JC polyomavirus (JCPyV) is a human-specific polyomavirus that establishes a silent lifelong infection in multiple peripheral organs, predominantly those of the urinary tract, of immunocompetent individuals. In immunocompromised settings, however, JCPyV can infiltrate the central nervous system (CNS), where it causes several encephalopathies of high morbidity and mortality. JCPyV-induced progressive multifocal leukoencephalopathy (PML), a devastating demyelinating brain disease, was an AIDS-defining illness before antiretroviral therapy that has "reemerged" as a complication of immunomodulating and chemotherapeutic agents. No effective anti-polyomavirus therapeutics are currently available. How depressed immune status sets the stage for JCPyV resurgence in the urinary tract, how the virus evades pre-existing antiviral antibodies to become viremic, and where/how it enters the CNS are incompletely understood. Addressing these questions requires a tractable animal model of JCPyV CNS infection. Although no animal model can replicate all aspects of any human disease, mouse polyomavirus (MuPyV) in mice and JCPyV in humans share key features of peripheral and CNS infection and antiviral immunity. In this review, we discuss the evidence suggesting how JCPyV migrates from the periphery to the CNS, innate and adaptive immune responses to polyomavirus infection, and how the MuPyV-mouse model provides insights into the pathogenesis of JCPyV CNS disease.
Topics: Humans; Animals; Mice; Polyomavirus; Leukoencephalopathy, Progressive Multifocal; JC Virus; Polyomavirus Infections; Brain Diseases
PubMed: 37896889
DOI: 10.3390/v15102112 -
Sultan Qaboos University Medical Journal Feb 2024Trichodysplasia spinulosa (TS) is a unique, rare clinical and histological dermatologic entity described mainly in a setting of immunosuppression. It is caused by a...
Trichodysplasia spinulosa (TS) is a unique, rare clinical and histological dermatologic entity described mainly in a setting of immunosuppression. It is caused by a novel human polymoavirus, TS-associated polyomavirus. Reduction of immunosuppression and/or anti-viral therapy is the main therapeutic strategies used to treat such cases. We report a biopsy-proven case of TS in a male renal transplant patient who presented to a dermatology outpatient clinic in Montreal, Canada, in 2015. He was managed with valgancyclovir with no obvious response. Subsequently, a trial of topical imiquimod was commenced. Awareness of TS can prompt early diagnosis and management to prevent possible complications.
Topics: Humans; Male; Biopsy; Canada; Skin Diseases
PubMed: 38434466
DOI: 10.18295/squmj.5.2023.035 -
The Journal of Clinical Investigation Sep 2023The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII...
The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and -2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and α6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.
Topics: Mice; Animals; Humans; Female; Collagen Type XVIII; Breast Neoplasms; Phosphatidylinositol 3-Kinases; Receptor, ErbB-2; Cell Transformation, Neoplastic; Signal Transduction
PubMed: 37498672
DOI: 10.1172/JCI159181 -
Genes & Diseases Nov 2023Virus-related cancer is cancer where viral infection leads to the malignant transformation of the host's infected cells. Seven viruses (e.g., human papillomavirus (HPV),... (Review)
Review
Virus-related cancer is cancer where viral infection leads to the malignant transformation of the host's infected cells. Seven viruses (e.g., human papillomavirus (HPV), Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T-lymphotropic virus (HTLV), and Merkel cell polyomavirus (MCV)) that infect humans have been identified as an oncogene and have been associated with several human malignancies. Recently, growing attention has been attracted to exploring the pathogenesis of virus-related cancers. One of the most mysterious molecules involved in carcinogenesis and progression of virus-related cancers is circular RNAs (circRNA). These emerging non-coding RNAs (ncRNAs), due to the absence of 5' and 3' ends, have high stability than linear RNAs and are found in some species across the eukaryotic organisms. Compelling evidence has revealed that viruses also encode a repertoire of circRNAs, as well as dysregulation of these viral circRNAs play a critical role in the pathogenesis and progression of different types of virus-related cancers. Therefore, understanding the exact role and function of the virally encoded circRNAs with virus-associated cancers will open a new road for increasing our knowledge about the RNA world. Hence, in this review, we will focus on emerging roles of virus-encoded circRNAs in multiple cancers, including cervical cancer, gastric cancer, Merkel cell carcinoma, nasopharyngeal carcinoma, Kaposi cancer, and liver cancer.
PubMed: 37554189
DOI: 10.1016/j.gendis.2022.04.009 -
Frontiers in Cellular and Infection... 2023The identification of the first human polyomavirus BK (BKV) has been over half century, The previous epidemiological and phylogenetic studies suggest that BKV prevailed... (Review)
Review
The identification of the first human polyomavirus BK (BKV) has been over half century, The previous epidemiological and phylogenetic studies suggest that BKV prevailed and co-evolved with humans, leading to high seroprevalence all over the world. In general, BKV stays latent and symptomless reactivation in healthy individuals. BKV has been mainly interlinked with BKV-associated nephropathy (BKVAN) in kidney-transplant recipients and hemorrhagic cystitis (HC) in hematopoietic stem cell transplant recipients (HSCTRs). However, the mechanisms underlying BKV latency and reactivation are not fully understood and lack of extensive debate. As Merkel cell polyomavirus (MCV) was identified as a pathogenic agent of malignant cutaneous cancer Merkel cell carcinoma (MCC) since 2008, linking BKV to tumorigenesis of urologic tumors raised concerns in the scientific community. In this review, we mainly focus on advances of mechanisms of BKV latency and reactivation, and BKV-associated diseases or tumorigenesis with systematical review of formerly published papers following the PRISMA guidelines. The potential tumorigenesis of BKV in two major types of cancers, head and neck cancer and urologic cancer, was systematically updated and discussed in depth. Besides, BKV may also play an infectious role contributing to HIV-associated salivary gland disease (HIVSGD) presentation. As more evidence indicates the key role of BKV in potential tumorigenesis, it is important to pay more attention on its etiology and pathogenicity and .
Topics: Humans; BK Virus; Phylogeny; Seroepidemiologic Studies; Polyomavirus Infections; Carcinogenesis; Cell Transformation, Neoplastic
PubMed: 37771695
DOI: 10.3389/fcimb.2023.1263983 -
JAMA Network Open Feb 2024Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with...
IMPORTANCE
Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with sepsis.
OBJECTIVE
To assess the association of the presence of viral DNA with sepsis-related mortality in a large multicenter study.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study compares pediatric patients with and without plasma cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6), parvovirus B19 (B19V), BK polyomavirus (BKPyV), human adenovirus (HAdV), and torque teno virus (TTV) DNAemia detected by quantitative real-time polymerase chain reaction or plasma IgG antibodies to CMV, EBV, HSV-1, or HHV-6. A total of 401 patients younger than 18 years with severe sepsis were enrolled from 9 pediatric intensive care units (PICUs) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Data were collected from 2015 to 2018. Samples were assayed from 2019 to 2022. Data were analyzed from 2022 to 2023.
MAIN OUTCOMES AND MEASURES
Death while in the PICU.
RESULTS
Among the 401 patients included in the analysis, the median age was 6 (IQR, 1-12) years, and 222 (55.4%) were male. One hundred fifty-four patients (38.4%) were previously healthy, 108 (26.9%) were immunocompromised, and 225 (56.1%) had documented infection(s) at enrollment. Forty-four patients (11.0%) died in the PICU. Viral DNAemia with at least 1 virus (excluding TTV) was detected in 191 patients (47.6%) overall, 63 of 108 patients (58.3%) who were immunocompromised, and 128 of 293 (43.7%) who were not immunocompromised at sepsis onset. After adjustment for age, Pediatric Risk of Mortality score, previously healthy status, and immunocompromised status at sepsis onset, CMV (adjusted odds ratio [AOR], 3.01 [95% CI, 1.36-6.45]; P = .007), HAdV (AOR, 3.50 [95% CI, 1.46-8.09]; P = .006), BKPyV (AOR. 3.02 [95% CI, 1.17-7.34]; P = .02), and HHV-6 (AOR, 2.62 [95% CI, 1.31-5.20]; P = .007) DNAemia were each associated with increased mortality. Two or more viruses were detected in 78 patients (19.5%), with mortality among 12 of 32 (37.5%) who were immunocompromised and 9 of 46 (19.6%) who were not immunocompromised at sepsis onset. Herpesvirus seropositivity was common (HSV-1, 82 of 246 [33.3%]; CMV, 107 of 254 [42.1%]; EBV, 152 of 251 [60.6%]; HHV-6, 253 if 257 [98.4%]). After additional adjustment for receipt of blood products in the PICU, EBV seropositivity was associated with increased mortality (AOR, 6.10 [95% CI, 1.00-118.61]; P = .049).
CONCLUSIONS AND RELEVANCE
The findings of this cohort study suggest that DNAemia for CMV, HAdV, BKPyV, and HHV-6 and EBV seropositivity were independently associated with increased sepsis mortality. Further investigation of the underlying biology of these viral DNA infections in children with sepsis is warranted to determine whether they only reflect mortality risk or contribute to mortality.
Topics: Adolescent; Humans; Male; Child; Infant; Child, Preschool; Female; DNA, Viral; Cohort Studies; Epstein-Barr Virus Infections; Herpesvirus 4, Human; DNA Viruses; Sepsis; Herpesvirus 1, Human; Cytomegalovirus Infections
PubMed: 38407904
DOI: 10.1001/jamanetworkopen.2024.0383 -
Frontiers in Pediatrics 2023Pediatric solid organ transplant is a life-saving procedure for children with end-stage organ failure. Viral infections are a common complication following pediatric... (Review)
Review
Pediatric solid organ transplant is a life-saving procedure for children with end-stage organ failure. Viral infections are a common complication following pediatric solid organ transplantation (SOT), which can lead to increased morbidity and mortality. Pediatric solid organ transplant recipients are at an increased risk of viral infections due to their immunosuppressed state. The most commonly encountered viruses include cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), adenoviruses, and BK polyomavirus. Prevention strategies include vaccination prior to transplantation, post-transplant prophylaxis with antiviral agents, and preemptive therapy. Treatment options vary depending on the virus and may include antiviral therapy and sometimes immunosuppression modification. This review provides a Quick Algorithmic overview of prevention and treatment strategies for viral infectious diseases in pediatric solid organ transplant recipient.
PubMed: 37732007
DOI: 10.3389/fped.2023.1252495