Immune responses of human T lymphocytes to novel hepatitis B virus-derived peptides

Yamamiya, Daisuke; Mizukoshi, Eishiro; Kaji, Kenzo; Terashima, Toshio; Kitahara, Masaaki; Yamashita, Tatsuya; Arai, Kuniaki; Fushimi, Kazumi; Honda, Masao

doi:10.1371/journal.pone.0198264

Cited by 10 publications

(6 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It would now be interesting to investigate how responses to these epitope variants relate in CHB patients, especially since p755-764 has been the only HBV-derived epitope described for supertype HLA-A*24 until very recently. For HLA-A*24:02, we studied the binding capacity of 3 peptides that were recently assessed for the first time in another study (89). Those authors did not detect cytotoxic T cells against p146-154 and p387-395, which fits our finding that neither peptide bound HLA-A*24:02.…”

Section: Discussionsupporting

confidence: 73%

Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength

Beijer

Jansen

Dou

et al. 2020

J Virol

View full text Add to dashboard Cite

Immunotherapy represents an attractive option for the treatment of chronic hepatitis B virus (HBV) infection. The HBV proteins polymerase (Pol) and HBx are of special interest for antigen-specific immunotherapy because they are essential for viral replication and have been associated with viral control (Pol) or are still expressed upon viral DNA integration (HBx). Here, we scored all currently described HBx- and Pol-derived epitope sequences for viral indispensability and conservation across all HBV genotypes. This yielded 7 HBx-derived and 26 Pol-derived reported epitopes with functional association and high conservation. We subsequently predicted novel HLA-binding peptides for 6 HLA supertypes prevalent in HBV-infected patients. Potential epitopes expected to be the least prone to immune escape were subjected to a state-of-the-art in vitro assay to validate their HLA-binding capacity. Using this method, a total of 13 HLA binders derived from HBx and 33 binders from Pol were identified across HLA types. Subsequently, we demonstrated interferon gamma (IFN-γ) production in response to 5 of the novel HBx-derived binders and 17 of the novel Pol-derived binders. In addition, we validated several infrequently described epitopes. Collectively, these results specify a set of highly potent T cell epitopes that represent a valuable resource for future HBV immunotherapy design. IMPORTANCE Multiple HBV-derived T cell epitopes have been reported, which can be useful in a therapeutic vaccination strategy. However, these epitopes are largely restricted to HLA-A*02, which is not dominantly expressed in populations with high HBV prevalence. Thus, current epitopes are falling short in the development of a global immunotherapeutic approach. Therefore, we aimed to identify novel epitopes for 6 HLA supertypes most prevalent in the infected population. Moreover, established epitopes might not all be equally effective as they can be subject to different levels of immune escape. It is therefore important to identify targets that are crucial in viral replication and conserved in the majority of the infected population. Here, we applied a stringent selection procedure to compose a combined overview of existing and novel HBV-derived T cell epitopes most promising for viral eradication. This set of T cell epitopes now lays the basis for the development of globally effective HBV antigen-specific immunotherapies.

show abstract

Section: Discussionsupporting

confidence: 73%

Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength

Beijer

Jansen

Dou

et al. 2020

J Virol

View full text Add to dashboard Cite

show abstract

“…T cells attacking targeted cells mainly depends on that TCR recognize T-cell epitopes, which are expressed, naturally processed and presented by MHC molecules on the cell surface [24]. In order to improve the probability of the predicted epitopes being presented by MHC class I, the predicted peptides were linked into the tandem minigenes, and fused with N-terminal leader peptide and C-terminal MITD, which have been proved to strongly improve the presentation of MHC class I and class II epitopes [25].…”

Section: Resultsmentioning

confidence: 99%

“…Spots were imaged and counted by an ELISPOT Reader (BioReader 4000, BIOSYS). Positive response was judged according to that the number of specific spots was more than 10 and at least two-fold greater than that of negative control [24].…”

Section: Methodsmentioning

confidence: 99%

The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

Liang

Qin

et al. 2019

Preprint

View full text Add to dashboard Cite

23Colorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the 24 world, as the result of the traditional treatments. Immunotherapy targeting neoantigens 25 can induce durable tumor regression in cancer patients, but is almost limited to 26 individual treatment, resulting from the unique neoantigens. Many shared oncogenic 27 mutations are detected, but whether the common neoantigens can be identified in CRC 28 is unknown. Using the somatic mutations data from 321 CRC patients combined with 29 a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-30 A*11:01 restricted common neoantigens with high binding affinity (IC50<50 nM) and 31 presentation score (EPIC>0.9). Except the positive epitope KRAS_G12V8-16, 11 out of 32 25 common neoantigens were proved to be naturally processed and presented on 33 constructed K562 cell surface by mass spectroscopy (MS), and 11 out of 25 common 34 neoantigens specifically induced in vitro pre-stimulated cytotoxic lymphocyte (CTL) 35 to secrete IFN-. However, only 2 out of 25 common neoantigens were simultaneously 36 presented and immunogenic. Moreover, using cell-sorting technology combined with 37 single-cell RNA sequencing, the immune repertoire profiles of C1orf170_S418G413-421 38 and KRAS_G12V8-16-specific CTL were clarified. Therefore, common neoantigens 39 with presentation and immunogenicity could be found in CRC, which would be 40 developed as the universal targets for CRC immunotherapy. 41 42 43 44 45 46 Colorectal cancer (CRC) is the third commonest diagnosed malignant cancer and 47 the second leading cause of cancer death in the world [1]. In 2018, more than 1.8 48 million new cases of CRC and almost 881 thousand cases of CRC-interrelated death 49 occurred in the world [1], and the global burden of CRC is estimated to reach over 2.2 50 million new cases and 1.1 million cancer deaths by 2030 [2]. Traditionally surgical 51 resection can cure the early stage of CRC, but about 50% of patients ultimately die of 52 distant metastases. While chemotherapy, radiation therapy and targeted therapy can 53 extend overall survival, less than 15% of patients with metastatic CRC survive 54 beyond 5 years [3]. Therefore, the novel and more effective therapeutic approaches 55 for CRC are necessary to develop. 56 In the recent years, based on a better knowledge of the complex interactions 57 between the immune system and the tumor microenvironment, immunotherapy has 58 become a novel effective and promising therapeutic strategy for cancer, and its 59 efficacy was widely tested by CRC model. The vast majority of CRC patients with 60 deficient mismatch repair (dMMR) or highly microsatellite instable (MSI-H) benefit 61 from immune checkpoint inhibitors, which is not effective in other CRC patients with 62 proficient MMR (pMMR) or microsatellite stable (MSS) [4]. Patients with CRC do 63 not respond to autologous tumour lysate DC (ADC) and peptide vaccines [4]. T cells, 64 which are engineered to express an affinity-enhanced T-cell rece...

show abstract

“…In ELISPOT analysis, a positive response was the number of spots (more than 10 spots) detected at least two-fold of the negative control 33 . In TCR-T cytotoxic activity test, the statistical analysis and graphical presentations were computed by GraphPad Prism software (GraphPad Software Inc.).…”

Section: Methodsmentioning

confidence: 99%

A pilot study of lymphodepletion intensity for peripheral blood mononuclear cell-derived neoantigen-specific CD8 + T cell therapy in patients with advanced solid tumors

Chen

et al. 2023

Nat Commun

View full text Add to dashboard Cite

Currently, the optimal lymphodepletion intensity for peripheral blood mononuclear cell-derived neoantigen-specific CD8 + T cell (Neo-T) therapy has yet to be determined. We report a single-arm, open-label and non-randomized phase 1 study (NCT02959905) of Neo-T therapy with lymphodepletion at various dose intensity in patients with locally advanced or metastatic solid tumors that are refractory to standard therapies. The primary end point is safety and the secondary end points are disease control rate (DCR), progression-free survival (PFS), overall survival (OS). Results show that the treatment is well tolerated with lymphopenia being the most common adverse event in the highest-intensity lymphodepletion groups. Neo-T infusion-related adverse events are only grade 1–2 in the no lymphodepletion group. The median PFS is 7.1 months (95% CI:3.7-9.8), the median OS is 16.8 months (95% CI: 11.9-31.7), and the DCR is 66.7% (6/9) among all groups. Three patients achieve partial response, two of them are in the no lymphodepletion group. In the group without lymphodepletion pretreatment, one patient refractory to prior anti-PD1 therapy shows partial response to Neo-T therapy. Neoantigen specific TCRs are examined in two patients and show delayed expansion after lymphodepletion treatment. In summary, Neo-T therapy without lymphodepletion could be a safe and promising regimen for advanced solid tumors.

show abstract

Immune responses of human T lymphocytes to novel hepatitis B virus-derived peptides

Cited by 10 publications

References 30 publications

Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength

Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength

The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

A pilot study of lymphodepletion intensity for peripheral blood mononuclear cell-derived neoantigen-specific CD8 + T cell therapy in patients with advanced solid tumors

Contact Info

Product

Resources

About