scholarly journals Uncovering the Tumor Antigen Landscape: What to Know about the Discovery Process

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1660
Author(s):  
Sara Feola ◽  
Jacopo Chiaro ◽  
Beatriz Martins ◽  
Vincenzo Cerullo
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Tumor Antigens ◽  
T Cell Response ◽  
Antigenic Peptides ◽  
T Cell Epitopes ◽  
Antigen Discovery ◽  
Future Challenges ◽  
Major Bottleneck ◽  
Therapeutic Cancer Vaccines

According to the latest available data, cancer is the second leading cause of death, highlighting the need for novel cancer therapeutic approaches. In this context, immunotherapy is emerging as a reliable first-line treatment for many cancers, particularly metastatic melanoma. Indeed, cancer immunotherapy has attracted great interest following the recent clinical approval of antibodies targeting immune checkpoint molecules, such as PD-1, PD-L1, and CTLA-4, that release the brakes of the immune system, thus reviving a field otherwise poorly explored. Cancer immunotherapy mainly relies on the generation and stimulation of cytotoxic CD8 T lymphocytes (CTLs) within the tumor microenvironment (TME), priming T cells and establishing efficient and durable anti-tumor immunity. Therefore, there is a clear need to define and identify immunogenic T cell epitopes to use in therapeutic cancer vaccines. Naturally presented antigens in the human leucocyte antigen-1 (HLA-I) complex on the tumor surface are the main protagonists in evocating a specific anti-tumor CD8+ T cell response. However, the methodologies for their identification have been a major bottleneck for their reliable characterization. Consequently, the field of antigen discovery has yet to improve. The current review is intended to define what are today known as tumor antigens, with a main focus on CTL antigenic peptides. We also review the techniques developed and employed to date for antigen discovery, exploring both the direct elution of HLA-I peptides and the in silico prediction of epitopes. Finally, the last part of the review analyses the future challenges and direction of the antigen discovery field.

scholarly journals Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein

2017 ◽  
Vol 1 ◽  
pp. 22
Author(s):  
Bryony Jenkins ◽  
Urszula Eksmond ◽  
George Young ◽  
George Kassiotis
Keyword(s):  
T Cell ◽  
Envelope Glycoprotein ◽  
Cell Epitope ◽  
Lymphocyte Activation ◽  
T Cell Response ◽  
Antigenic Peptides ◽  
T Cell Epitopes ◽  
Immunosuppressive Activity ◽  
Histocompatibility Complex ◽  
Antigenic Epitopes

To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs) of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II), and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of pMHC formation or TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.

scholarly journals Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein

2016 ◽  
Vol 1 ◽  
pp. 22
Author(s):  
Bryony Jenkins ◽  
Urszula Eksmond ◽  
George Young ◽  
George Kassiotis
Keyword(s):  
T Cell ◽  
Envelope Glycoprotein ◽  
Cell Epitope ◽  
Lymphocyte Activation ◽  
T Cell Response ◽  
Antigenic Peptides ◽  
T Cell Epitopes ◽  
Immunosuppressive Activity ◽  
Histocompatibility Complex ◽  
Antigenic Epitopes

To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs) of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II), and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.

scholarly journals Selecting Target Antigens for Cancer Vaccine Development

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 615 ◽  
Author(s):  
Luigi Buonaguro ◽  
Maria Tagliamonte
Keyword(s):  
T Cell ◽  
Cancer Vaccine ◽  
Cancer Vaccines ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
T Cell Response ◽  
Therapeutic Cancer Vaccine ◽  
Memory T Cell ◽  
Heteroclitic Peptides ◽  
Therapeutic Cancer Vaccines

One of the principal goals of cancer immunotherapy is the development of efficient therapeutic cancer vaccines that are able to elicit an effector as well as memory T cell response specific to tumor antigens. In recent years, the attention has been focused on the personalization of cancer vaccines. However, the efficacy of therapeutic cancer vaccines is still disappointing despite the large number of vaccine strategies targeting different tumors that have been evaluated in recent years. While the preclinical data have frequently shown encouraging results, clinical trials have not provided satisfactory data to date. The main reason for such failures is the complexity of identifying specific target tumor antigens that should be unique or overexpressed only by the tumor cells compared to normal cells. Most of the tumor antigens included in cancer vaccines are non-mutated overexpressed self-antigens, eliciting mainly T cells with low-affinity T cell receptors (TCR) unable to mediate an effective anti-tumor response. In this review, the target tumor antigens employed in recent years in the development of therapeutic cancer vaccine strategies are described, along with potential new classes of tumor antigens such as the human endogenous retroviral elements (HERVs), unconventional antigens, and/or heteroclitic peptides.

scholarly journals Characterisation of the T-cell response to Ebola virus glycoprotein amongst survivors of the 2013–16 West Africa epidemic

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
T. R. W. Tipton ◽  
Y. Hall ◽  
J. A. Bore ◽  
A. White ◽  
L. S. Sibley ◽  
...  
Keyword(s):  
T Cell ◽  
West Africa ◽  
Cell Response ◽  
Ebola Virus ◽  
Medical Condition ◽  
Virus Disease ◽  
T Cell Response ◽  
Ebola Virus Disease ◽  
Cell Phenotype ◽  
T Cell Epitopes

AbstractZaireebolavirus (EBOV) is a highly pathogenic filovirus which can result in Ebola virus disease (EVD); a serious medical condition that presents as flu like symptoms but then often leads to more serious or fatal outcomes. The 2013–16 West Africa epidemic saw an unparalleled number of cases. Here we show characterisation and identification of T cell epitopes in surviving patients from Guinea to the EBOV glycoprotein. We perform interferon gamma (IFNγ) ELISpot using a glycoprotein peptide library to identify T cell epitopes and determine the CD4+ or CD8+ T cell component response. Additionally, we generate data on the T cell phenotype and measure polyfunctional cytokine secretion by these antigen specific cells. We show candidate peptides able to elicit a T cell response in EBOV survivors and provide inferred human leukocyte antigen (HLA) allele restriction. This data informs on the long-term T cell response to Ebola virus disease and highlights potentially important immunodominant peptides.

T-cell epitopes within the complementarity-determining and framework regions of the tumor-derived immunoglobulin heavy chain in multiple myeloma

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4930-4936 ◽  
Author(s):  
Lotta Hansson ◽  
Hodjattallah Rabbani ◽  
Jan Fagerberg ◽  
Anders Österborg ◽  
Håkan Mellstedt
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Heavy Chain ◽  
T Cell Response ◽  
Class I ◽  
Type I ◽  
T Cell Epitopes ◽  
Hla Binding

Abstract The idiotypic structure of the monoclonal immunoglobulin (Ig) in multiple myeloma (MM) might be regarded as a tumor-specific antigen. The present study was designed to identify T-cell epitopes of the variable region of the Ig heavy chain (VH) in MM (n = 5) using bioinformatics and analyze the presence of naturally occurring T cells against idiotype-derived peptides. A large number of human-leukocyte-antigen (HLA)–binding (class I and II) peptides were identified. The frequency of predicted epitopes depended on the database used: 245 in bioinformatics and molecular analysis section (BIMAS) and 601 in SYFPEITHI. Most of the peptides displayed a binding half-life or score in the low or intermediate affinity range. The majority of the predicted peptides were complementarity-determining region (CDR)–rather than framework region (FR)–derived (52%-60% vs 40%-48%, respectively). Most of the predicted peptides were confined to the CDR2-FR3-CDR3 “geographic” region of the Ig-VH region (70%), and significantly fewer peptides were found within the flanking (FR1-CDR1-FR2 and FR4) regions (P < .01). There were 8– to 10–amino acid (aa) long peptides corresponding to the CDRs and fitting to the actual HLA-A/B haplotypes that spontaneously recognized, albeit with a low magnitude, type I T cells (interferon γ), indicating an ongoing major histocompatibility complex (MHC) class I–restricted T-cell response. Most of those peptides had a low binding half-life (BIMAS) and a low/intermediate score (SYFPEITHI). Furthermore, 15- to 20-aa long CDR1-3–derived peptides also spontaneously recognized type I T cells, indicating the presence of MHC class II–restricted T cells as well. This study demonstrates that a large number of HLA-binding idiotypic peptides can be identified in patients with MM. Such peptides may spontaneously induce a type I MHC class I– as well as class II–restricted memory T-cell response.

scholarly journals Immunodominance in Mouse and Human CD4+ T-Cell Responses Specific for the Bordetella pertussis Virulence Factor P.69 Pertactin

2008 ◽  
Vol 77 (2) ◽  
pp. 896-903 ◽  
Author(s):  
Rachel M. Stenger ◽  
Martien C. M. Poelen ◽  
Ed E. Moret ◽  
Betsy Kuipers ◽  
Sven C. M. Bruijns ◽  
...  
Keyword(s):  
T Cell ◽  
Bordetella Pertussis ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Cell Immunity ◽  
Hla Dq ◽  
Natural Variants ◽  
Acellular Vaccines

ABSTRACT P.69 pertactin (P.69 Prn), an adhesion molecule from the causative agent of pertussis, Bordetella pertussis, is present in cellular and most acellular vaccines that are currently used worldwide. Although both humoral immunity and cellular immunity directed against P.69 Prn have been implicated in protective immune mechanisms, the identities of CD4+ T-cell epitopes on the P.69 Prn protein remain unknown. Here, a single I-Ad-restricted B. pertussis conserved CD4+ T-cell epitope at the N terminus of P.69 Prn was identified by using a BALB/c T-cell hybridoma. The epitope appeared immunodominant among four other minor strain-conserved P.69 Prn epitopes recognized after vaccination and B. pertussis infection, and it was capable of evoking a Th1/Th17-type cytokine response. B. pertussis P.69 Prn immune splenocytes did not cross-react with natural variants of the epitope as present in Bordetella parapertussis and Bordetella bronchiseptica. Finally, it was found that the immunodominant P.69 Prn epitope is broadly recognized in the human population by CD4+ T cells in an HLA-DQ-restricted manner. During B. pertussis infection, the epitope was associated with a Th1-type CD4+ T-cell response. Hence, this novel P.69 Prn epitope is involved in CD4+ T-cell immunity after B. pertussis vaccination and infection in mice and, more importantly, in humans. Thus, it may provide a useful tool for the evaluation of the type, magnitude, and maintenance of B. pertussis-specific CD4+ T-cell mechanisms in preclinical and clinical vaccine studies.

scholarly journals 793 Targeting engineered interleukin-2 (IL-2) to antigen specific T cells via novel biologic platforms

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A828-A828
Author(s):  
Raymond Moniz ◽  
Ahmet Vakkasoglu ◽  
Zohra Merazga ◽  
Tina Daigneault ◽  
Steve Quayle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Interleukin 2 ◽  
Binding Pocket ◽  
Tumor Escape ◽  
Antigenic Peptides ◽  
T Cell Epitopes ◽  
Cell Repertoire

BackgroundA key challenge with IL-2 immunotherapy for cancers is lack of selectivity for anti-tumor immune cells and safety liabilities related to indiscriminate activation of immune cells. The CUE-100 series of Immuno-STATs (ISTs) are designed to selectively activate tumor-specific T cells while avoiding IL-2 toxicities due to systemic activation. CUE-100 series ISTs are rationally engineered Fc fusion proteins comprised of bivalent tumor-peptide-HLA (pHLA) complexes and four affinity-attenuated IL-2 molecules to preferentially engage and activate tumor-specific T cells directly in the patient. Emerging clinical data from our lead candidate CUE-101, which targets HPV-specific T cells in 2L+ R/M HNSCCC, provides PoC for the approach and builds confidence for broad applications in numerous cancers. Building on the CUE-100 series framework, our Neo-STAT (NST) platform contains HLA molecules manufactured with an “empty” peptide-binding pocket, into which diverse tumor-peptides can be chemically conjugated, hence addressing tumor heterogeneity in a cost- and time-efficient manner. Our RDI-STAT (Re-Directed Immuno-STAT) platform further expands the CUE-100 series by redirecting the pre-existing protective viral-specific T cell repertoire to target tumor cells via scFv moieties. RDI-STATs are designed to circumvent potential tumor escape mechanisms linked to HLA loss or defects in antigen-presenting pathways. We present here preclinical data supporting the mechanism of action of these platforms to enhance anti-tumor immune responses.MethodsNSTs were engineered with “empty” HLA-A*0201, into which relevant antigenic peptides were conjugated, and assessed for capacity to expand T cells. RDI-STATs were engineered with TAA-specific scFv and viral-specific pHLA complexes, and assessed for their capacity to induce redirected killing of tumor cells while avoiding systemic activation of all T cells.ResultsThe NST platform demonstrated that different T cell epitopes can be efficiently conjugated into the HLA-binding pocket, and that these molecules activate and expand antigen specific T cells in vitro. RDI-STATs were able to expand anti-viral T cell repertoires and drive anti-viral T cell redirected killing of TAA-expressing cells. In contrast to pan anti-CD3 bispecific molecules, RDI-STATs demonstrated significantly lower induction of pro-inflammatory cytokines.ConclusionsThe IST, NST, and RDI-STAT platforms provide novel opportunities for selective targeting of IL-2 to tumor-relevant T cells while avoiding global immune activation and cytokine release. The scalability and versatility of NSTs highlight the potential to target multiple TAA T cell responses, while RDI-STATs highlight a novel means to harness antiviral immunity against cancer, especially in cases where the tumor may escape immune detection due to loss of HLA.

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.

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