scholarly journals HPV16 E6-specific T cell response and HLA-A alleles are related to the prognosis of patients with cervical cancer

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Hongchao Cai ◽  
Yaning Feng ◽  
Peiwen Fan ◽  
Yuping Guo ◽  
Gulina Kuerban ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Allele Distribution ◽  
Hpv16 E6 ◽  
Cox Regression Analysis ◽  
Cell Responses ◽  
E6 And E7

Abstract Background T cell epitopes are polypeptide fragments presented to T cell receptors by MHC molecules encoded by human leukocyte antigen (HLA) genes after antigen-presenting cell processing, which is the basis for the study of antigen immune mechanism and multi-epitope vaccine. This study investigated T cell response to HPV16 E6 and E7 in patients with cervical squamous cell carcinoma (CSCC). Also, the HLA-A allele distribution was compared among patients and evaluated as a factor to predict prognosis in these patients. Materials and methods This study recruited a total of 76 patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IIIB CSCC. Mononuclear cells were isolated from the peripheral blood before any treatment and then enzyme-linked immunosorbent spot (ELISpot) assay was employed to measure the E6 and E7-specific T cell response. HLA‐A alleles were typed using Sanger sequencing‐based typing techniques with DNA extracted from the peripheral blood. The correlation between the T cell responses, HLA‐A allele distribution and patient prognosis were analysed using the Kaplan–Meier method, univariate and multivariate Cox proportional hazard models. Results The frequency of HPV E6-specific T cell responses in patients with pelvic lymph node metastasis was lower than that in patients without metastasis (P = 0.022). The 5-year overall survival (OS) rates of patients were 87.5% for those responding to multiple overlapping peptides, 72.7% for those responding to 1–2 overlapping peptides and 47.7% for non-responders (P = 0.032). Cox regression analysis indicated that the presence of HLA*A02:07 was independently associated with worse OS (hazard ratio [HR] 3.042; 95% confidence interval [CI] 1.348–6.862; P = 0.007), while concurrent chemoradiation therapy (CCRT) was independently associated with better OS (HR 0.475; 95% CI 0.232–0.975; P = 0.042). Conclusion The results of our study demonstrated that the level of HPV16 E6-specific T cell response and HLA*A02:07 were correlated with prognosis in patients with advanced CSCC.

scholarly journals HPV16 E6-specific T Cell Response and HLA-A Alleles Are Related to the Prognosis of Patients With Cervical Cancer 

2021 ◽  
Author(s):  
Hongchao Cai ◽  
Yaning Feng ◽  
Peiwen Fan ◽  
Yuping Guo ◽  
Gulina Kuerban ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cell ◽  
Peripheral Blood ◽  
Cell Response ◽  
T Cell Response ◽  
Peptide Group ◽  
Allele Distribution ◽  
Hpv16 E6 ◽  
Cell Responses ◽  
E6 And E7

Abstract Background: It is worthwhile to identify more epitopes as target to design T cell-based therapeutic interventions that can benefit cervical cancer patients whose disease cannot be well controlled with current treatment modalities. This study investigated T cell response to HPV16 E6 and E7 in patients with cervical squamous cell carcinoma (CSCC). Also, the human leukocyte antigen (HLA)-A allele distribution was compared among patients and evaluated as factors to predict prognosis in these patients.Materials and Methods: This study recruited a total of 76 patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IIIB CSCC. Mononuclear cells were isolated from the peripheral blood before any treatment and then enzyme-linked immunosorbent spot (ELISpot) assay was employed to measure the E6 and E7-specific T cell response. HLA‐A alleles were typed using Sanger sequence‐based typing techniques with DNA extracted from the peripheral blood. The correlation between the T cell responses, HLA‐A allele distribution and patient prognosis were analysed using the Kaplan–Meier method, univariate and multivariate Cox proportional hazard models.Results: The frequency of HPV E6-specific T cell responses in patients with pelvic lymph node metastasis was lower than that in patients without metastasis (P=0.022). The 5-year overall survival (OS) rates of patients were 87.5% for the multiple overlapping peptide group, 72.7% for the 1–2 overlapping peptide group, and 47.7% for the negative group (P=0.032). Cox regression analysis indicated that the presence of HLA*A02:07 was independently associated with worse OS (hazard ratio [HR] 3.042; 95% confidence interval [CI]: 1.348–6.862; P=0.007), while concurrent chemoradiation therapy (CCRT) was independently associated with better OS (HR 0.475; 95% CI: 0.232–0.975; P= 0.042).Conclusion: The results of our study demonstrated that the level of HPV16 E6-specific T cell response and HLA*A02:07 were correlated with prognosis in patients with advanced CSCC.

scholarly journals Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response

2020 ◽  
Author(s):  
Anastasia Gangaev ◽  
Elisa A Rozeman ◽  
Maartje W Rohaan ◽  
Daisy Philips ◽  
Sanne Patiwael ◽  
...  
Keyword(s):  
T Cell ◽  
Mechanism Of Action ◽  
Peripheral Blood ◽  
Cell Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Tumor Site ◽  
Cell Responses ◽  
Melanoma Patients

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If activation of circulating tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses towards 71 melanoma associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the melanoma-reactive CD8 T cell response in peripheral blood was unaltered upon PD-1 blockade. In contrast, a broadening of the melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. On the basis of these results, we conclude that PD-1 and CTLA-4 blockade impact the tumor-reactive CD8 T cell response in a distinct manner. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.

scholarly journals Anaplasma marginale Infection with Persistent High-Load Bacteremia Induces a Dysfunctional Memory CD4+ T Lymphocyte Response but Sustained High IgG Titers

2010 ◽  
Vol 17 (12) ◽  
pp. 1881-1890 ◽  
Author(s):  
Sushan Han ◽  
Junzo Norimine ◽  
Kelly A. Brayton ◽  
Guy H. Palmer ◽  
Glen A. Scoles ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Persistent Infection ◽  
Peripheral Blood ◽  
Cell Response ◽  
T Cell Responses ◽  
Anaplasma Marginale ◽  
High Load ◽  
T Cell Response ◽  
Cell Responses

ABSTRACT Control of blood-borne infections is dependent on antigen-specific effector and memory T cells and high-affinity IgG responses. In chronic infections characterized by a high antigen load, it has been shown that antigen-specific T and B cells are vulnerable to downregulation and apoptosis. Anaplasma marginale is a persistent infection of cattle characterized by acute and chronic high-load bacteremia. We previously showed that CD4+ T cells primed by immunization with an A. marginale outer membrane protein were rapidly deleted following infection. Furthermore, peripheral blood T cell responses to bacteria were not observed after acute infection was controlled, suggesting dysfunctional T cell priming to other A. marginale antigens. The current study more closely investigated the kinetics of A. marginale-specific CD4+ T cell responses primed during infection. Frequent sampling of peripheral blood and spleens revealed that antigen-specific CD4+ T cell responses were first detected at 5 to 7 weeks, but the responses were sporadic and transient thereafter. A similar pattern was observed in animals sampled weekly for nearly 1 year. Paradoxically, by 2 weeks of infection, cattle had developed high titers of A. marginale-specific IgG, which remained high throughout persistent infection. This dysfunctional CD4+ T cell response to infection is consistent with continual downregulation or deletion of newly primed effector T cells, similar to what was observed for immunization-induced T cells following A. marginale infection. The failure to establish a strong memory T cell response during A. marginale infection likely contributes to bacterial persistence.

scholarly journals T cell phenotypes in COVID-19

2020 ◽  
Author(s):  
Stephanie J Hanna ◽  
Amy S Codd ◽  
Ester Gea-Mallorqui ◽  
D Oliver Scourfield ◽  
Felix C Richter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Immune Memory ◽  
Cell Responses ◽  
T Cell Phenotypes ◽  
Cell Phenotypes

Abstract COVID-19 is characterised by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterised by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients’ long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2 specific T cells to elucidate markers which may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that whilst some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation.

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.

scholarly journals Listeria Monocytogenes: A Model Pathogen Continues to Refine Our Knowledge of the CD8 T Cell Response

Pathogens ◽  
2018 ◽  
Vol 7 (2) ◽  
pp. 55 ◽  
Author(s):  
Zhijuan Qiu ◽  
Camille Khairallah ◽  
Brian Sheridan
Keyword(s):  
Listeria Monocytogenes ◽  
T Cell ◽  
Cell Response ◽  
Protective Immunity ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Oral Infection ◽  
T Cell Response ◽  
Infection Model ◽  
Cell Responses

Listeria monocytogenes (Lm) infection induces robust CD8 T cell responses, which play a critical role in resolving Lm during primary infection and provide protective immunity to re-infections. Comprehensive studies have been conducted to delineate the CD8 T cell response after Lm infection. In this review, the generation of the CD8 T cell response to Lm infection will be discussed. The role of dendritic cell subsets in acquiring and presenting Lm antigens to CD8 T cells and the events that occur during T cell priming and activation will be addressed. CD8 T cell expansion, differentiation and contraction as well as the signals that regulate these processes during Lm infection will be explored. Finally, the formation of memory CD8 T cell subsets in the circulation and in the intestine will be analyzed. Recently, the study of CD8 T cell responses to Lm infection has begun to shift focus from the intravenous infection model to a natural oral infection model as the humanized mouse and murinized Lm have become readily available. Recent findings in the generation of CD8 T cell responses to oral infection using murinized Lm will be explored throughout the review. Finally, CD8 T cell-mediated protective immunity against Lm infection and the use of Lm as a vaccine vector for cancer immunotherapy will be highlighted. Overall, this review will provide detailed knowledge on the biology of CD8 T cell responses after Lm infection that may shed light on improving rational vaccine design.

scholarly journals Public T-cell epitopes shared among SARS-CoV-2 variants are presented on prevalent HLA class I alleles

2021 ◽  
Author(s):  
Saskia Meyer ◽  
Isaac Blaas ◽  
Ravi Chand Bollineni ◽  
Marina Delic-Sarac ◽  
Trung T Tran ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Class I ◽  
T Cell Epitopes ◽  
Low Frequencies ◽  
Cell Responses

T-cell epitopes with broad population coverage may form the basis for a new generation of SARS-CoV-2 vaccines. However, published studies on immunoprevalence are limited by small test cohorts, low frequencies of antigen-specific cells and lack of data correlating eluted HLA ligands with T-cell responsiveness. Here, we investigate CD8 T-cell responses to 48 peptides eluted from prevalent HLA alleles, and an additional 84 predicted binders, in a large cohort of convalescents (n=83) and pre-pandemic control samples (n=19). We identify nine conserved SARS-CoV-2 specific epitopes restricted by four of the most prevalent HLA class I alleles in Caucasians, to which responding CD8 T cells are detected in 70-100% of convalescents expressing the relevant HLA allele, including two novel epitopes. We find a strong correlation between immunoprevalence and immunodominance. Using a new algorithm, we predict that a vaccine including these epitopes would induce a T cell response in 83% of Caucasians. Significance Statement: Vaccines that induce broad T-cell responses may boost immunity as protection from current vaccines against SARS-CoV-2 is waning. From a manufacturing standpoint, and to deliver the highest possible dose of the most immunogenic antigens, it is rational to limit the number of epitopes to those inducing the strongest immune responses in the highest proportion of individuals in a population. Our data show that the CD8 T cell response to SARS-CoV-2 is more focused than previously believed. We identify nine conserved SARS-CoV-2 specific CD8 T cell epitopes restricted by four of the most prevalent HLA class I alleles in Caucasians and demonstrate that seven of these are endogenously presented.

scholarly journals Mononucleosis and Antigen-Driven T Cell Responses Have Different Requirements for Interleukin-2 Signaling in Murine Gammaherpesvirus Infection

2010 ◽  
Vol 84 (20) ◽  
pp. 10923-10927 ◽  
Author(s):  
Michael Molloy ◽  
Weijun Zhang ◽  
Edward Usherwood
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
T Cell Response ◽  
Long Term Memory ◽  
Murine Gammaherpesvirus ◽  
Cell Responses ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Interleukin-2 (IL-2) has been implicated as being necessary for the optimal formation of primary CD8+ T cell responses against various pathogens. Here we have examined the role that IL-2 signaling plays in several aspects of a CD8+ T cell response against murine gammaherpesvirus 68 (MHV-68). Exposure to MHV-68 causes a persistent infection, along with infectious mononucleosis, providing a model for studying these processes in mice. Our study indicates that CD25 is necessary for optimal expansion of the antigen-specific CD8+ T cell response but not for the long-term memory response. Contrastingly, IL-2 signaling through CD25 is absolutely required for CD8+ T cell mononucleosis.

scholarly journals DNA gag/Adenovirus Type 5 (Ad5) gag and Ad5 gag/Ad5 gag Vaccines Induce Distinct T-Cell Response Profiles

2008 ◽  
Vol 82 (16) ◽  
pp. 8161-8171 ◽  
Author(s):  
Kara S. Cox ◽  
James H. Clair ◽  
Michael T. Prokop ◽  
Kara J. Sykes ◽  
Sheri A. Dubey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Adenovirus Type ◽  
T Cell Response ◽  
Cell Responses ◽  
Response Profiles ◽  
Adenovirus Type 5 ◽  
Hiv 1

ABSTRACT Results from Merck's phase II adenovirus type 5 (Ad5) gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against human immunodeficiency virus (HIV) infection in a high-risk population. Among the many questions to be explored following this outcome are whether (i) the Ad5 vaccine induced the quality of T-cell responses necessary for efficacy and (ii) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV type 1 (HIV-1)-specific T-cell responses. Here we present a comprehensive evaluation of the T-cell response profiles from cohorts of clinical trial subjects who received the HIV CAM-1 gag insert delivered by either a regimen with DNA priming followed by Ad5 boosting (n = 50) or a homologous Ad5/Ad5 prime-boost regimen (n = 70). The samples were tested using a statistically qualified nine-color intracellular cytokine staining assay measuring interleukin-2 (IL-2), tumor necrosis factor alpha, macrophage inflammatory protein 1β, and gamma interferon production and expression of CD107a. Both vaccine regimens induced CD4+ and CD8+ HIV gag-specific T-cell responses which variably expressed several intracellular markers. Several trends were observed in which the frequencies of HIV-1-specific CD4+ T cells and IL-2 production from antigen-specific CD8+ T cells in the DNA/Ad5 cohort were more pronounced than in the Ad5/Ad5 cohort. Implications of these results for future vaccine development will be discussed.

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