scholarly journals Expansion of Human Papillomavirus-Specific T Cells in Periphery and Cervix in a Therapeutic Vaccine Recipient Whose Cervical High-Grade Squamous Intraepithelial Lesion Regressed

2020 ◽  
Author(s):  
Takeo Shibata ◽  
Sumit Shah ◽  
Teresa Evans ◽  
Hannah Coleman ◽  
Benjamin J. Lieblong ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
Mononuclear Cells ◽  
Therapeutic Vaccine ◽  
T Cell Response ◽  
High Grade ◽  
Squamous Intraepithelial Lesion ◽  
Before And After ◽  
Intraepithelial Lesion

AbstractAdvances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) β deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. Interferon-γ enzyme-linked immunospot assay identified significantly increased HPV-specific T cell response in the HPV 16 E6 91-115 region after 4 vaccinations (p=0.023). T cells with specificity to this region were sorted and analyzed using single-cell RNA-seq and TCR sequencing, HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR β bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells in the periphery and cervix.

scholarly journals Expansion of Human Papillomavirus-Specific T Cells in Periphery and Cervix in a Therapeutic Vaccine Recipient Whose Cervical High-Grade Squamous Intraepithelial Lesion Regressed

2021 ◽  
Vol 12 ◽  
Author(s):  
Takeo Shibata ◽  
Sumit Shah ◽  
Teresa Evans ◽  
Hannah Coleman ◽  
Benjamin J. Lieblong ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
High Throughput Sequencing ◽  
Mononuclear Cells ◽  
Therapeutic Vaccine ◽  
High Grade ◽  
Squamous Intraepithelial Lesion ◽  
Before And After ◽  
Intraepithelial Lesion

Advances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) β deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. In order to verify the vaccine-specificity of these clonotypes, T cells with specificity to a region, HPV 16 E6 91-115, previously identified to be vaccine-induced using an interferon-γ enzyme-linked immunospot assay, were sorted and analyzed using single-cell RNA-seq and TCR sequencing. HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR β bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells not only in the periphery but also in the cervix. Such an approach should be useful as a novel approach to assess vaccine-specific responses in various anatomical areas.

Expression of RHAMM and WT1 As Well As T Cell Responses to These Antigens Before and After Allogeneic Stem Cell Transplantation in Patients with Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4315-4315
Author(s):  
Rosaely Casalegno-Garduño ◽  
Claudia Meier ◽  
Jiju Mani ◽  
Kersten Borchert ◽  
Inken Hilgendorf ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Before And After

Abstract Abstract 4315 Introduction: Patients with leukemia undergo chemotherapy as first treatment. Approximately 70–80% of patients with acute myeloid leukemia (AML) reach complete remission. However, most of them will relapse and only 25% survive more than five years. Therefore, there is a need for novel approaches in the treatment of leukemia, such as immunotherapy. Leukemic blasts have an aberrant expression of antigens. They are called leukemia-associated antigens (LAAs) like the receptor for hyaluronan acid-mediated motility (RHAMM) and the Wilms’ tumor gene 1 product (WT1). Epitopes of these LAAs can be recognized by CD8+ T cells. MATERIAL AND METHODS: In the present study, we analyzed the correlation between the clinical course of 18 patients suffering from leukemia (10 AML, 5 MDS, 1 ALL and 2 B-CLL) with the expression of RHAMM and WT1 transcripts before and after allogeneic stem cell transplantation (allo-SCT). Gene transcripts were measured by quantitative real time PCR (RQ-PCR) from RNA of peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) samples. Antigen specific T cells were enriched in a mixed lymphocyte-peptide culture (MLPC) and antigen specific T cell responses were measured by enzyme-linked immunosorbent spot (ELISPOT). Results: We observed a reduction in WT1 transcripts in both PBMC and BMMC after transplantation in all of the WT1 positive patients (6/18 patients: 33%). Four of these six WT1+ patients (67%) remained in complete remission (CR) with low transcripts of WT1 (PBMC: lower than 14 WT1 copies/104 ABL copies, BMMC: lower than 202 WT1 copies/104 ABL copies). In contrast, 2 of 6 WT1+ patients (33%) showed an increase (PBMC: up to 98 WT1 copies/104 ABL copies, BMMC: up to 920 WT1 copies/104 ABL copies) of WT1 transcripts eventually resulting in a relapse. Specific T cell responses were detected against WT1 in two of three WT1+ patients in the presence of blasts (before transplantation or in relapse). However, these specific responses vanished while the patients reached a CR. Furthermore, RHAMM+ patients (12/18: 67%) showed different patterns when correlated with clinical status. Five patients (42%) showed gradually increased levels of RHAMM transcripts during CR. No RHAMM specific T cells could be detected in this group (2/2 MLPCs). Four patients (33%) showed a decrease in the transcripts of RHAMM when they reached a CR. One of these patients developed a T cell response to RHAMM three months after allo-SCT (2/2 MLPCs). One patient showed high transcripts of RHAMM and WT1 during the diagnosis, WT1 transcripts were reduced after allo-SCT. Both RHAMM and WT1 transcripts gradually increased until the patients died. We could detect in this patient both WT1 and RHAMM-specific T cells before transplantation. After allo-SCT the T cell response vanished. CONCLUSION: Taken together, WT1 is a suitable marker for minimal residual disease after allo-SCT. One might speculate that T cells specific for WT1 vanished during the CR due to the absence of the antigen to stimulate the proliferation of specific T cell population. Moreover, the presence of RHAMM-specific T cells may help to maintain a CR. In both cases vaccination with RHAMM and WT1 derived peptide might enhance T cell responses in the patient leading to a better outcome of the patient. Disclosures: Freund: Medac: Honoraria, Research Funding.

Impact of human papillomavirus coinfections on the risk of high-grade squamous intraepithelial lesion and cervical cancer

2014 ◽  
Vol 134 (3) ◽  
pp. 534-539 ◽  
Author(s):  
Adela Carrillo-García ◽  
Sergio Ponce-de-León-Rosales ◽  
David Cantú-de-León ◽  
Verónica Fragoso-Ontiveros ◽  
Imelda Martínez-Ramírez ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Grade ◽  
Squamous Intraepithelial Lesion ◽  
Intraepithelial Lesion

Evaluation of Dynamic Thiol-Disulfide Balance in Preinvasive Lesions of the Cervix

2021 ◽  
Author(s):  
Burak Sezgin ◽  
Fatih Pirinççi ◽  
Aysun Camuzcuoğlu ◽  
Eda Adeviye Şahin ◽  
Özcan Erel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Papillomavirus ◽  
Stress Index ◽  
Lesion Group ◽  
Control Group ◽  
High Grade ◽  
Squamous Intraepithelial Lesion ◽  
Oxidative Stress Index ◽  
Preinvasive Lesions ◽  
Intraepithelial Lesion

Abstract Purpose: This study aimed to determine the potential clinical use of dynamic thiol disulfide balance in cases with preinvasive lesions of the cervix.Methods: One hundred and sixteen patients with high-grade squamous intraepithelial lesion, one hundred patients with low-grade squamous intraepithelial lesion and one hundred and ten healthy controls were enrolled in the study. A fully automated colorimetric system was used to determine the levels of thiol-disulfide parameters. The ischemia-modified albumin, total oxidant-antioxidant capacity, oxidative stress index of the retrieved cases were further analysed.Results: Native thiol and total thiol levels are significantly lower in the high-grade squamous intraepithelial lesion group according to control group (p:0.004 and p:0.015, respectively). Disulfide level is significantly increased in the high-grade squamous intraepithelial lesion group compared to control group (p:0.004). Oxidative stress index levels in high-grade squamous intraepithelial lesion group were observed as significantly higher according to the control group (p:0.014). Ischemia-modified albumin levels in the high-grade squamous intraepithelial lesion group were observed as significantly higher compared to the control group (p:0.020). Disulfide levels are positively correlated with risk type of Human papillomavirus (r:0.420, p<0.001).Conclusion: The analysis of dynamic thiol disulfide balance revealed considerable oxidative damage in patients with Human papillomavirus -related cervical precursor lesions compared to women with ordinary cytology specimens. Therefore, investigation of thiol disulfide balance with presented method represents a new promising test for early diagnosis and management of women at high risk for cervical cancer.

scholarly journals Convergent epitope-specific T cell responses after SARS-CoV-2 infection and vaccination

2021 ◽  
Author(s):  
Anastasia A Minervina ◽  
Mikhail V Pogorelyy ◽  
Allison M Kirk ◽  
Emma Kaitlynn Allen ◽  
Kim J Allison ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Critical Parameters ◽  
T Cell Memory ◽  
Cell Memory ◽  
Cell Responses ◽  
Depth Analysis

SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

scholarly journals HPV-16 E7-Specific Cellular Immune Response in Women With Cervical Intraepithelial Lesion Contributes to Viral Clearance: A Cross-Sectional and Longitudinal Clinical Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Lina Zhang ◽  
Xinyi Shi ◽  
Qing Zhang ◽  
Zhilei Mao ◽  
Xiaoyu Shi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Hpv Infection ◽  
T Cell Response ◽  
Viral Clearance ◽  
Low Grade ◽  
High Grade ◽  
Cross Sectional ◽  
Intraepithelial Lesion ◽  
Longitudinal Clinical Study

High-risk human papillomavirus (HPV) infection is the cause of almost all cervical cancers. HPV16 is one of the main risk subtypes. Although screening programs have greatly reduced the prevalence of cervical cancer in developed countries, current diagnostic tests cannot predict if mild lesions may progress into invasive lesions or not. In the current cross-sectional and longitudinal clinical study, we found that the HPV16 E7-specific T cell response in peripheral blood mononuclear cells of HPV16-infected patients is related to HPV16 clearance. It contributes to protecting the squamous interaepithelial lesion (SIL) from further malignant development. Of the HPV16 infected women enrolled (n = 131), 42 had neither intraepithelial lesion nor malignancy (NILM), 33 had low-grade SIL, 39 had high-grade SIL, and 17 had cervical cancer. Only one of 17 (5.9%) cancer patients had a positive HPV16 E7-specific T cell response, dramatically lower than the groups of precancer patients. After one year of follow-up, most women (28/33, 84.8%) with persistent HPV infection did not exhibit a HPV16 E7-specific T cell response. Furthermore, 3 malignantly progressed women, one progressed to high-grade SIL and two progressed to low-grade SIL, were negative to the HPV16 E7-specific T cell response. None of the patients with a positive HPV16 E7-specific T cell response progressed to further deterioration. Our observation suggests that HPV16 E7-specific T cell immunity is significant in viral clearance and contributes in protection against progression to malignancy.

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