scholarly journals A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates

2018 ◽  
Author(s):  
Miguel J. Rodo ◽  
Virginie Rozot ◽  
Elisa Nemes ◽  
One Dintwe ◽  
Mark Hatherill ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Vaccine Candidates ◽  
Memory T Cell ◽  
Response Characteristics ◽  
Cell Responses ◽  
Efficacy Trials

AbstractEradication of tuberculosis (TB), the world’s leading cause of death due to infectious disease, requires a highly efficacious TB vaccine. Many TB vaccine candidates are in preclinical and clinical development but only a few can be advanced to large-scale efficacy trials due to limited global resources. We aimed to perform a statistically rigorous comparison of the antigen-specific T cell responses induced by six novel TB vaccine candidates and the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG). We propose that the antigen-specific immune response induced by such vaccines provides an objective, data-driven basis for prioritisation of vaccine candidates for efficacy testing. We analyzed frequencies of antigen-specific CD4 and CD8 T cells expressing IFNγ, IL-2, TNF and/or IL-17 from adolescents or adults, with or without Mycobacterium tuberculosis (M.tb) infection, who received MVA85A, AERAS-402, H1:IC31, H56:IC31, M72/AS01E, ID93+GLA-SE or BCG. Two key response characteristics were analyzed, namely response magnitude and cytokine co-expression profile of the memory T cell response that persisted above the pre-vaccination response to the final study visit in each trial. All vaccines preferentially induced antigen-specific CD4 T cell responses expressing Th1 cytokines; levels of IL-17-expressing cells were low or not detected. In M.tb-uninfected and ‐infected individuals, M72/AS01E induced higher memory Th1 cytokine-expressing CD4 T cell responses than other novel vaccine candidates. Cytokine co-expression profiles of memory CD4 T cells induced by different novel vaccine candidates were alike. Our study suggests that the T cell response feature which most differentiated between the TB vaccine candidates was response magnitude, whilst functional profiles suggested a lack of response diversity. Since M72/AS01E induced the highest memory CD4 T cell response it demonstrated the best vaccine take. In the absence of immunological correlates of protection the likelihood of finding a protective vaccine by empirical testing of candidates may be increased by the addition of candidates that induce distinct immune characteristics.Author summaryTuberculosis (TB) causes more deaths than any other single infectious disease, and a new, improved vaccine is needed to control the epidemic. Many new TB vaccine candidates are in clinical development, but only one or two can be advanced to expensive efficacy trials. In this study, we compared magnitude and functional attributes of memory T cell responses induced in recently conducted clinical trials by six TB vaccine candidates, as well as BCG. The results suggest that these vaccines induced CD4 and CD8 T cell responses with similar functional attributes, but that one vaccine, M72/AS01E, induced the largest responses. This finding may indicate a lack of diversity in T cell responses induced by different TB vaccine candidates. A repertoire of vaccine candidates that induces more diverse immune response characteristics may increase the chances of finding a protective vaccine against TB.

scholarly journals Broadly directed SARS-CoV-2-specific CD4+ T cell response includes frequently detected peptide specificities within the membrane and nucleoprotein in patients with acute and resolved COVID-19

2021 ◽  
Vol 17 (9) ◽  
pp. e1009842
Author(s):  
Janna Heide ◽  
Sophia Schulte ◽  
Matin Kohsar ◽  
Thomas Theo Brehm ◽  
Marissa Herrmann ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Ex Vivo ◽  
Intracellular Cytokine Staining ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Single Peptide

The aim of this study was to define the breadth and specificity of dominant SARS-CoV-2-specific T cell epitopes using a comprehensive set of 135 overlapping 15-mer peptides covering the SARS-CoV-2 envelope (E), membrane (M) and nucleoprotein (N) in a cohort of 34 individuals with acute (n = 10) and resolved (n = 24) COVID-19. Following short-term virus-specific in vitro cultivation, the single peptide-specific CD4+ T cell response of each patient was screened using enzyme linked immuno spot assay (ELISpot) and confirmed by single-peptide intracellular cytokine staining (ICS) for interferon-γ (IFN-γ) production. 97% (n = 33) of patients elicited one or more N, M or E-specific CD4+ T cell responses and each patient targeted on average 21.7 (range 0–79) peptide specificities. Overall, we identified 10 N, M or E-specific peptides that showed a response frequency of more than 36% and five of them showed high binding affinity to multiple HLA class II binders in subsequent in vitro HLA binding assays. Three peptides elicited CD4+ T cell responses in more than 55% of all patients, namely Mem_P30 (aa146-160), Mem_P36 (aa176-190), both located within the M protein, and Ncl_P18 (aa86-100) located within the N protein. These peptides were further defined in terms of length and HLA restriction. Based on this epitope and restriction data we developed a novel DRB*11 tetramer (Mem_aa145-164) and examined the ex vivo phenotype of SARS-CoV-2-specific CD4+ T cells in one patient. This detailed characterization of single T cell peptide responses demonstrates that SARS-CoV-2 infection universally primes a broad T cell response directed against multiple specificities located within the N, M and E structural protein.

Characterization of a double-CRD-mutated Gal-8 recombinant protein that retains co-stimulatory activity on antigen-specific T-cell response

2016 ◽  
Vol 473 (7) ◽  
pp. 887-898 ◽  
Author(s):  
Matías Nicolás Schroeder ◽  
María Virginia Tribulatti ◽  
Julieta Carabelli ◽  
Gwenaëlle André-Leroux ◽  
Julio Javier Caramelo ◽  
...  
Keyword(s):  
T Cell ◽  
Recombinant Protein ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Stimulatory Activity ◽  
Terminal Domains

The development and characterization of a Gal-8 protein where both N- and C-terminal domains were modified in order to display altered glycan recognition, allowed the discrimination of distinctive effects exerted by Gal-8 on CD4+ T-cell responses.

scholarly journals SARS-CoV-2-specific T cell memory is long-lasting in the majority of convalsecent COVID-19 individuals

2020 ◽  
Author(s):  
Ziwei Li ◽  
Jing Liu ◽  
Hui Deng ◽  
Xuecheng Yang ◽  
Hua Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Onset ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Long Term Memory ◽  
Memory T Cell ◽  
Cell Responses ◽  
Cell Immunity

ABSTRACTAn unaddressed key question in the current coronavirus disease 2019 (COVID-19) pandemic is the duration of immunity for which specific T cell responses against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an indispensable element. Being situated in Wuhan where the pandemic initiated enables us to conduct the longest analyses of memory T cell responses against SARS-CoV-2 in COVID-19 convalescent individuals (CIs). Magnitude and breadth of SARS-CoV-2 memory CD4 and CD8 T cell responses were heterogeneous between patients but robust responses could be detected up to 9 months post disease onset in most CIs. Loss of memory CD4 and CD8 T cell responses were observed in only 16.13% and 25.81% of CIs, respectively. Thus, the overall magnitude and breadth of memory CD4 and CD8 T cell responses were quite stable and not inversely correlated with the time from disease onset. Interestingly, the only significant decrease in the response was found for memory CD4 T cells in the first 6-month post COVID-19 disease onset. Longitudinal analyses revealed that the kinetics of SARS-CoV-2 memory CD4 and CD8 T cell responses were quite heterogenous between patients. Loss of memory CD4 T cell responses was observed more frequently in asymptomatic cases than after symptomatic COVID-19. Interestingly, the few CIs in which SARS-CoV-2-specific IgG responses disappeared showed more durable memory CD4 T cell responses than CIs who remained IgG-positive for month. Collectively, we provide the first comprehensive characterization of the long-term memory T cell response in CIs, suggesting that SARS-CoV-2-specific T cell immunity is long-lasting in the majority of individuals.

Analysis of EBV-Specific T Cell Responses in Transplant Recipients with PTLD.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1915-1915
Author(s):  
Kathrin Sebelin ◽  
Antje Meier ◽  
Matthias Papp-Vary ◽  
Stefan Oertel ◽  
Antonio Pezzutto ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cell Response ◽  
Low Frequency ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses

Abstract EBV causes a chronic infection in >95 % of the population and despite its strong growth transforming capacity the majority of EBV infected individuals remain asymptomatic. In contrary, in immunosuppressed patients (pts) the risk of EBV reactivation and development of posttransplant lymphoproliferative disease (PTLD) is high. This is assumed to be due to a defective T cell response. Here we analyzed the EBV-specific CD8 and CD4 T cell response to different EBV latent and lytic antigens in pts with newly diagnosed PTLD. A prospective study of 10 pts after solid organ transplantation at time of diagnosis of PTLD was performed. EBV-specific CD8 T cells were examined by flow cytometric analysis using HLA-A2, HLA-B7 and HLA-B8 restricted tetramers incorporating BMLF1 (lytic), EBNA3 and LMP2 (both latent)-derived peptides. Staining was done in conjunction with mAbs against CD8 and CCR7. The ability of CD8 T cells to produce IFN-γ in response to the same EBV-derived peptides was measured by cytokine secretion assay. In healthy, EBV+ donors, we previously have found a consistent CD4 T cell response to the latent EBV antigen EBNA1. Therefore, EBNA1-specific CD4 T cell responses were monitored for IFN-g / IL-4 secretion after protein stimulation. T cell analysis was combined with EBV-DNA quantiation by real time PCR. We found EBV-specific CD8 T cell responses at low frequency in most pts with PTLD (8/10). Half of the pts showed low frequency EBNA1 specific CD4+ T cell responses. All pts with an EBNA1 specific CD4 T cell response showed an EBV-specific CD8 T cell response. In 2/10 pts we found no EBV-specific CD4 and CD8 T cell responses and both pts died under initial therapy. EBV-viral load was found to inversely correlate to absolute CD4 T cell counts. In comparison to healthy normal donors, no significant differences in EBV-specific T cell response could be observed. However, pts EBV-specific T cells were decreased in comparison to pts with high EBV viral load after TX and no PTLD as well as in comparison to pts with infectious mononucleosis. These results indicate that impairment of EBV-specific T cells is not due to clonal depletion, but rather seems to be due to impaired functional activation and expansion. We therefore conclude that pts with PTLD have an inadequatly low EBV-specific T cell responses which correlates to a low absolute CD4 T cell count. We propose a combined immunomonitoring of EBV viral load, absolute CD4 T cell count and EBV-specific T cell enumeration in pts at risk for development of PTLD. Further studies are needed to evaluate the role of EBV-specific T cell monitoring in immunosuppressed pts for prediction of PTLD and the potential usefulness of T cell monitoring as a prognostic marker in PTLD.

A Novel Splenocyte Approach for Characterizing T Cell Responses to Adeno-Associated Virus in the Normal Population: Implications on Gene Transfer.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3258-3258
Author(s):  
Daniel J. Hui ◽  
Federico Mingozzi ◽  
Marcela V. Maus ◽  
Michael A. Tigges ◽  
Glenn F. Pierce ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Transfer ◽  
Cell Response ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
T Cell Response ◽  
Normal Donor ◽  
Memory T Cell ◽  
Cell Responses

Abstract Gene transfer using adeno-associated viral (AAV) vectors offers a promising strategy for the treatment of hemophilia B. However, in the first clinical trial using AAV-2 to deliver Factor IX (F.IX) into the liver via the hepatic artery, transgene expression was short-lived, followed by a gradual decline in F.IX levels and a transient rise in liver enzymes (Manno et al., 2006). We hypothesize this outcome was caused by a memory T cell response to a previous infection with wild-type AAV-2, which led to T cell-mediated destruction of transduced hepatocytes upon recognition of capsid sequences during gene transfer. No immune response to F.IX was detected. In order to further investigate the role that previous exposure to AAV-2 may have on limiting the duration of gene transfer, a normal donor population consisting of 46 adult subjects was tested for AAV-2 neutralizing antibodies and frequencies of circulating capsid-specific T cells by ELISpot assay. More than half (25/46) of the subjects had readily detectable titers of neutralizing antibodies to AAV-2 in serum. However, the prevalence of AAV-2 capsid-specific T cells detected by IFN-γ ELISpot in PBMCs was very low and positive responses could be confirmed in only 2/46 subjects. Attempts to expand the relevant T cell population in vitro, in which PBMCs were stimulated with the relevant AAV-2 peptide epitope, did not increase the frequency of detectable T cell responses. These results suggest that current methods may not be sensitive enough to fully appreciate the prevalence of AAV-2-specific CD8+ memory T cells in humans because they circulate at frequencies that are commonly too low for detection, as indicated by the discrepancy between the presence of AAV neutralizing antibodies and the observed T cell response. Moreover, it is possible that AAV-specific CD8+ T cells fail to circulate but rather reside in lymphatic compartments. To address this problem, we developed an alternative approach using human splenocytes. Splenocytes offer two critical advantages: they permit sampling of a primary lymphoid organ, and they can be obtained in much higher overall cell numbers than PBMCs. Using splenocytes obtained from both normal donor adults and children undergoing splenectomy, T cell responses via ELISpot assay have been detected in 7 out of 27 subjects, reflecting a higher frequency (26%) of observed T cell responses than that seen using PBMCs. In addition, intracellular cytokine staining analysis for IFN-γ confirmed the presence of AAV capsid-specific CD8+ T cells in the samples tested. Interestingly, in the current study T cell responses were seen in donors as young as 5 years of age, while more robust responses were seen in adult patients >37 years of age. These results have important implications for gene transfer with AAV; specifically, that children as young as 5 years old have detectable T cell responses to AAV capsid and could thus mount a memory T cell response on vector infusion. We conclude that memory T-cell-mediated immune responses to viral capsids in the normal population is more common than PBMC-based assays suggest, and given the observed cross-reactivity among AAV serotypes (see abstract by Mingozzi et al.), these results may affect not only AAV-2 clinical trials, but other AAV clinical trials as well.

NY-ESO-1 Vaccination in Combination with Decitabine for Patients with MDS Induces CD4+ and CD8+ T-Cell Responses

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2873-2873 ◽  
Author(s):  
Pragya Srivastava ◽  
Junko Matsuzaki ◽  
Benjamin E. Paluch ◽  
Zachary Brumberger ◽  
Stephanie Kaufman ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Promoter Methylation ◽  
Cell Response ◽  
Research Funding ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses

Abstract Background: Identification of suitable target antigens for immunotherapy has been a challenge in patients with myeloid malignancies. NY-ESO-1 has been identified as an immunotherapeutic target in solid tumors. Its use in myeloid cancer is limited due to silencing by dense promoter hypermethylation. We and others have demonstrated that decitabine can induce expression of NY-ESO-1 in leukemia cell lines. We hypothesized that vaccination against NY-ESO-1 in combination with decitabine would be safe and result in NY-ESO-1 expression sufficient to induce NY-ESO-1 specific humoral and cellular immune responses in treatment-na•ve myelodysplastic syndrome (MDS) patients. Methods: We performed a phase I trial of NY-ESO-1 vaccine (anti-DEC-205-NY-ESO-1 fusion protein (CDX-1401) with poly-ICLC adjuvant; Celldex Therapeutics) in combination with decitabine (20 mg/m2/day x 5 days). Patients with intermediate/high-risk MDS by IPSS, > 18 years old, ECOG performance status < 2, and adequate hepatic and renal function were enrolled on an IRB-approved protocol (median age 64y). Patients with uncontrolled medical illness, HIV-positivity, auto-immunity or recent corticosteroid/radiation therapy were excluded. All patients signed informed consent and were treated in accordance with the Declaration of Helsinki. Patients were vaccinated on day -14, received decitabine on day 1 and were re-vaccinated on day 14 of each cycle. Four cycles of therapy were planned. Peripheral blood was obtained pre-treatment, twice weekly, and at end of treatment (EOT). CD11b+ myeloid cells were isolated from each sample. Immune monitoring was performed at baseline and at EOT. An interim analysis, pre-specified in the protocol for the first 6 patients, was planned for safety and immunology endpoints. Three additional patients enrolled to an expansion cohort to ensure sufficient power for correlative studies remain on treatment. Results: Analysis of the initial safety cohort showed no unexpected toxicities. The most frequent adverse events were related to decitabine and included cytopenias (predominantly grades 3/4), elevated liver enzymes (grade 3), fatigue (grade 2), edema (grade 2/3) and diarrhea (grade 1/2). Two patients did not complete four cycles of therapy due to serious adverse events; 1 patient with a history of myocardial infarction (MI) developed in-stent restenosis and recurrent MI; a second patient suffered a terminal intracranial hemorrhage due to thrombocytopenia (deemed decitabine related). LINE-1 (surrogate for global methylation) and NY-ESO-1 promoter methylation in the CD11b+ myeloid population were serially quantified for the first 2 patients by bisulfite pyrosequencing. The methylation nadir for LINE-1 and NY-ESO-1 occurred between days 8 and 15 of each decitabine cycle. Changes in LINE-1 and NY-ESO-1 methylation were correlated for each patient (R2 = 0.95, p < 0.001). Expression of NY-ESO-1 mRNA (by nested RT-PCR) was performed on CD11b+ cells from days 0, 8, 15, and 22 of the first cycle for these two patients. Patient 1 exhibited NY-ESO-1 mRNA on days 8 and 15. Patient 2 did not show any NY-ESO-1 expression. Of the first 6 patients analyzed, none showed baseline humoral immunity to NY-ESO-1 and seroconversion was observed in one subject (Table 1). Five patients had induced NY-ESO-1 specific CD4+ T-cell responses and 4 patients had NY-ESO-1 specific CD8+ T-cell responses following vaccination. Table 1. Response to Vaccination. T cell response assessed by ELISPOT for IFN-g and scored after subtracting background. Numbers in parentheses indicate number of epitopes recognized by T cells. Bold type indicates responses induced or enhanced by vaccination. Patient ID Antibody response CD4+ T cell response CD8+ T cell response Pre Post Pre Post Pre Post 1 - + ++ (2) +++ (3) - (0) + (1) 2 - - - (0) + (2) - (0) - (0) 3 - - - (0) + (2) - (0) + (1) 4 - - - (0) + (1) - (0) - (0) 5 - - - (0) + (1) - (0) + (2) 6 - - + (1) - (0) - (0) ++ (3) Conclusion: Vaccination against NY-ESO-1 is safe in combination with decitabine. Circulating myeloid cells exhibited decreased NY-ESO-1 promoter methylation. 1 of 2 sampled patients demonstrated induction of NY-ESO-1 mRNA in the myeloid compartment. Vaccination successfully induced CD4+ and CD8+ T-cell responses in a majority of patients. These data indicate that vaccination against NY-ESO-1 in combination with decitabine is feasible, opening the door for future studies targeting this induced antigen in MDS. Disclosures Wang: Immunogen: Research Funding. Griffiths:Celgene: Honoraria; Alexion Pharmaceuticals: Honoraria; Astex: Research Funding.

Analysis of HIV-1–  and CMV-specific memory CD4 T-cell responses during primary and chronic infection

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1381-1387 ◽  
Author(s):  
Alexandre Harari ◽  
G. Paolo Rizzardi ◽  
Kim Ellefsen ◽  
Donatella Ciuffreda ◽  
Patrick Champagne ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cmv Infection ◽  
Cell Responses ◽  
Specific Memory ◽  
Hiv 1

CD4 T-cell–specific memory antiviral responses to human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) were investigated in 16 patients with documented primary HIV-1 infection (4 of the 16 subjects also had primary CMV infection) and compared with those observed in patients with chronic HIV-1 and CMV coinfection. Virus-specific memory CD4 T cells were characterized on the basis of the expression of the chemokine receptor CCR7. HIV-1– and CMV-specific interferon-γ–secreting CD4 T cells were detected in patients with primary and chronic HIV-1 and CMV coinfection and were mostly contained in the cell population lacking expression of CCR7. The magnitude of the primary CMV-specific CD4 T-cell response was significantly greater than that of chronic CMV infection, whereas there were no differences between primary and chronic HIV-1–specific CD4 T-cell responses. A substantial proportion of CD4+CCR7− T cells were infected with HIV-1. These results advance the characterization of antiviral memory CD4 T-cell response and the delineation of the potential mechanisms that likely prevent the generation of a robust CD4 T-cell immune response during primary infection.

scholarly journals Strain-Specific T-Cell Suppression and Protective Immunity in Patients with Chronic Hepatitis C Virus Infection

2005 ◽  
Vol 79 (11) ◽  
pp. 6976-6983 ◽  
Author(s):  
Kazushi Sugimoto ◽  
David E. Kaplan ◽  
Fusao Ikeda ◽  
Jin Ding ◽  
Jonathan Schwartz ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Genotype 2

ABSTRACT Hepatitis C virus (HCV) frequently persists with an apparently ineffective antiviral T-cell response. We hypothesized that some patients may be exposed to multiple HCV subtypes and that strain-specific T cells could contribute to the viral dynamics in this setting. To test this hypothesis, CD4 T-cell responses to three genotype 1a-derived HCV antigens and HCV antibody serotype were examined in chronically HCV infected (genotypes 1a, 1b, 2, 3, and 4) and spontaneously HCV recovered subjects. Consistent with multiple HCV exposure, 63% of patients infected with genotypes 2 to 4 (genotypes 2-4) and 36% of those infected with genotype 1b displayed CD4 T-cell responses to 1a-derived HCV antigens, while 29% of genotype 2-4-infected patients showed serotype responses to genotype 1. Detection of 1a-specific T cells in patients without active 1a infection suggested prior self-limited 1a infection with T-cell-mediated protection from 1a but not from non-1a viruses. Remarkably, CD4 T-cell responses to 1a-derived HCV antigens were weakest in patients with homologous 1a infection and greater in non-1a-infected patients: proportions of patients responding were 19% (1a), 36% (1b), and 63% (2-4) (P = 0.0006). Increased 1a-specific CD4 T-cell responsiveness in non-1a-infected patients was not due to increased immunogenicity or cross-reactivity of non-1a viruses but directly related to sequence divergence. We conclude that the T-cell response to the circulating virus is either suppressed or not induced in a strain-specific manner in chronically HCV infected patients and that, despite their ability to clear one HCV strain, patients may be reinfected with a heterologous strain that can then persist. These findings provide new insights into host-virus interactions in HCV infection that have implications for vaccine development.

scholarly journals Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322924
Author(s):  
Tuxiong Huang ◽  
Xiang-Yu Tan ◽  
Hui-Si Huang ◽  
Yu-Ting Li ◽  
Bei-Lei Liu ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Tumour Microenvironment ◽  
T Cell Response ◽  
Cell Responses ◽  
Cancer Associated Fibroblast ◽  
Anticancer Immunotherapy ◽  
Novel Therapeutic Strategies

ObjectiveSolid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC).DesignAnti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses.ResultsA negative correlation between WNT2+ CAFs and active CD8+ T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades.ConclusionsCAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

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