NEPdb: A Database of T-Cell Experimentally-Validated Neoantigens and Pan-Cancer Predicted Neoepitopes for Cancer Immunotherapy

T-cell recognition of somatic mutation-derived cancer neoepitopes can lead to tumor regression. Due to the difficulty to identify effective neoepitopes, constructing a database for sharing experimentally validated cancer neoantigens will be beneficial to precise cancer immunotherapy. Meanwhile, the routine neoepitope prediction in silico is important but laborious for clinical use. Here we present NEPdb, a database that contains more than 17,000 validated human immunogenic neoantigens and ineffective neoepitopes within human leukocyte antigens (HLAs) via curating published literature with our semi-automatic pipeline. Furthermore, NEPdb also provides pan-cancer level predicted HLA-I neoepitopes derived from 16,745 shared cancer somatic mutations, using state-of-the-art predictors. With a well-designed search engine and visualization modes, this database would enhance the efficiency of neoantigen-based cancer studies and treatments. NEPdb is freely available at http://nep.whu.edu.cn/.

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The Advances and Challenges of NK Cell-Based Cancer Immunotherapy

Current Oncology ◽

10.3390/curroncol28020105 ◽

2021 ◽

Vol 28 (2) ◽

pp. 1077-1093

Author(s):

Synat Kang ◽

Xuefeng Gao ◽

Li Zhang ◽

Erna Yang ◽

Yonghui Li ◽

...

Keyword(s):

Nk Cells ◽

Cancer Immunotherapy ◽

Nk Cell ◽

Tumor Development ◽

Human Leukocyte ◽

Cell Receptor ◽

Clinical Applications ◽

Therapeutic Approaches ◽

Leukocyte Antigens ◽

Recognition Specificity

Natural killer (NK) cells can be widely applied for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization or human leukocyte antigens-matching. Several NK-based therapeutic approaches have been attempted in clinical practice, but their efficacy is not sufficient to suppress tumor development mainly because of lacking specificity. To this end, the engineering of NK cells with T cell receptor along with CD3 subunits (TCR-NK) has been developed to increase the reactivity and recognition specificity of NK cells toward tumor cells. Here, we review recent advances in redirecting NK cells for cancer immunotherapy and discuss the major challenges and future explorations for their clinical applications.

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Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001439 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001439 ◽

Cited By ~ 1

Author(s):

Rafael Cubas ◽

Zia Khan ◽

Qian Gong ◽

Marina Moskalenko ◽

Huizhong Xiong ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Immunotherapy ◽

Phosphatase Activity ◽

Tumor Regression ◽

Checkpoint Inhibitors ◽

Therapeutic Option ◽

Interleukin 2 ◽

Cell Functions ◽

Increased Risk

BackgroundCancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.ResultsHere, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.ConclusionsTogether, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.

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HIV-1 Subtype C Gag-Specific T-Cell Responses in Relation to Human Leukocyte Antigens in a Diverse Population of HIV-Infected Ethiopians

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0b013e318059beaa ◽

2007 ◽

Vol 45 (4) ◽

pp. 389-400 ◽

Cited By ~ 1

Author(s):

Aster Tsegaye ◽

Leonie Ran ◽

Dawit Wolday ◽

Beyene Petros ◽

Wendelien Dorigo ◽

...

Keyword(s):

T Cell ◽

Human Leukocyte ◽

T Cell Responses ◽

Human Leukocyte Antigens ◽

Diverse Population ◽

Subtype C ◽

Cell Responses ◽

Leukocyte Antigens ◽

Hiv 1

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Immunotherapy of Cytotoxic T Cell–resistant Tumors by T Helper 2 Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021683 ◽

2003 ◽

Vol 197 (3) ◽

pp. 387-393 ◽

Cited By ~ 152

Author(s):

Joerg Mattes ◽

Mark Hulett ◽

Wei Xie ◽

Simon Hogan ◽

Marc E. Rothenberg ◽

...

Keyword(s):

T Cell ◽

Cancer Immunotherapy ◽

Tumor Regression ◽

Lung Metastases ◽

Specific Antigen ◽

Th2 Cells ◽

Cytotoxic T Cell ◽

Transcription Activator ◽

Secretion Profile ◽

Immunotherapy Of Cancer

Currently most attempts at cancer immunotherapy involve the generation of CD8+ cytotoxic T lymphocytes (CTLs) against tumor-associated antigens. Many tumors, however, have been immunoselected to evade recognition by CTLs and thus alternative approaches to cancer immunotherapy are urgently needed. Here we demonstrate that CD4+ T cells that recognize a secreted tumor-specific antigen and exhibit a cytokine secretion profile characteristic of Th2 cells, are capable of clearing established lung and visceral metastases of a CTL-resistant melanoma. Clearance of lung metastases by the Th2 cells was found to be totally dependent on the eosinophil chemokine, eotaxin, and partially dependent on the transcription activator signal transducer and activator of transcription 6 (STAT6), with degranulating eosinophils within the tumors inducing tumor regression. In contrast, tumor-specific CD4+ Th1 cells, that recruited macrophages into the tumors, had no effect on tumor growth. This work provides the basis for a new approach to adoptive T cell immunotherapy of cancer.

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Large-Scale Structure-Based Screening of Potential T Cell Cross-Reactivities Involving Peptide-Targets From BCG Vaccine and SARS-CoV-2

Frontiers in Immunology ◽

10.3389/fimmu.2021.812176 ◽

2022 ◽

Vol 12 ◽

Author(s):

Renata Fioravanti Tarabini ◽

Mauricio Menegatti Rigo ◽

André Faustino Fonseca ◽

Felipe Rubin ◽

Rafael Bellé ◽

...

Keyword(s):

T Cell ◽

Large Scale ◽

Vaccine Development ◽

Human Leukocyte ◽

Cross Reactivity ◽

Vaccination Programs ◽

Bcg Vaccination ◽

Leukocyte Antigens ◽

Infected Cells ◽

First Time

Although not being the first viral pandemic to affect humankind, we are now for the first time faced with a pandemic caused by a coronavirus. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been responsible for the COVID-19 pandemic, which caused more than 4.5 million deaths worldwide. Despite unprecedented efforts, with vaccines being developed in a record time, SARS-CoV-2 continues to spread worldwide with new variants arising in different countries. Such persistent spread is in part enabled by public resistance to vaccination in some countries, and limited access to vaccines in other countries. The limited vaccination coverage, the continued risk for resistant variants, and the existence of natural reservoirs for coronaviruses, highlight the importance of developing additional therapeutic strategies against SARS-CoV-2 and other coronaviruses. At the beginning of the pandemic it was suggested that countries with Bacillus Calmette-Guérin (BCG) vaccination programs could be associated with a reduced number and/or severity of COVID-19 cases. Preliminary studies have provided evidence for this relationship and further investigation is being conducted in ongoing clinical trials. The protection against SARS-CoV-2 induced by BCG vaccination may be mediated by cross-reactive T cell lymphocytes, which recognize peptides displayed by class I Human Leukocyte Antigens (HLA-I) on the surface of infected cells. In order to identify potential targets of T cell cross-reactivity, we implemented an in silico strategy combining sequence-based and structure-based methods to screen over 13,5 million possible cross-reactive peptide pairs from BCG and SARS-CoV-2. Our study produced (i) a list of immunogenic BCG-derived peptides that may prime T cell cross-reactivity against SARS-CoV-2, (ii) a large dataset of modeled peptide-HLA structures for the screened targets, and (iii) new computational methods for structure-based screenings that can be used by others in future studies. Our study expands the list of BCG peptides potentially involved in T cell cross-reactivity with SARS-CoV-2-derived peptides, and identifies multiple high-density “neighborhoods” of cross-reactive peptides which could be driving heterologous immunity induced by BCG vaccination, therefore providing insights for future vaccine development efforts.

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Human Leukocyte Antigens Class II Alleles Affecting the Response to 5–7 Year Antiretroviral Therapy in A Latvian Cohort

Proceedings of the Latvian Academy of Sciences Section B Natural Exact and Applied Sciences ◽

10.2478/prolas-2019-0014 ◽

2019 ◽

Vol 73 (2) ◽

pp. 84-88

Author(s):

Vladislavs Jasinskis ◽

Oksana Koļesova ◽

Aleksandrs Koļesovs ◽

Baiba Rozentāle ◽

Inga Ažiņa ◽

...

Keyword(s):

Viral Load ◽

T Cell ◽

Antiretroviral Therapy ◽

Cell Count ◽

Human Leukocyte ◽

Class Ii ◽

Hla Typing ◽

Human Leukocyte Antigens ◽

Leukocyte Antigens ◽

Hiv 1

Abstract Antiretroviral therapy (ART) aims at suppressing viral replication and strengthening immune system in patients with HIV-1. Human Leukocyte Antigens (HLA) are among factors responsible for effectiveness of ART. The aim of this study was to determine the effect of HLA Class II alleles on the response to long-time ART, assessed by a change in CD4+ T-cell count in relation to viral load. The sample included 69 patients (17 females and 52 males) aged 20 to 50 with HIV-1 infection, who were undergoing ART in the Latvian Centre of Infectious Diseases. The median period of observation was 5.7 years. CD4+ T-cell count and viral load were analysed at the baseline and end of the period of observation. HLA typing was performed by polymerase chain reaction with low resolution sequence specific primers. Multiple hierarchical linear regression analysis confirmed that an increase in HIV-1 viral load was associated with a decrease in the level of CD4+ T-cell count. In addition, HLA-DRB1*04 and HLA-DQB1*06:01 alleles contributed negatively to the level of CD4+ T-cell count.

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Enhanced target-specific delivery of docetaxel-loaded nanoparticles using engineered T cell receptors

Nanoscale ◽

10.1039/d1nr04001d ◽

2021 ◽

Author(s):

William Joseph McDaid ◽

Nikolai Lissin ◽

Ellen Pollheimer ◽

Michelle Greene ◽

Adam Leach ◽

...

Keyword(s):

Targeted Therapy ◽

T Cell ◽

Cancer Cells ◽

T Cell Receptors ◽

Human Leukocyte ◽

Human Leukocyte Antigens ◽

Cell Receptors ◽

Leukocyte Antigens

For effective targeted therapy of cancer with chemotherapy-loaded nanoparticles (NPs), antigens that are selective for cancer cells should be targeted to minimise off-tumour toxicity. Human leukocyte antigens (HLAs) are an...

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