Multiple Epitopes in the Murine Cytomegalovirus Early Gene Product M84 Are Efficiently Presented in Infected Primary Macrophages and Contribute to Strong CD8+-T-Lymphocyte Responses and Protection following DNA Immunization

ABSTRACT We previously demonstrated that after vaccination of BALB/c mice with DNA encoding murine cytomegalovirus (MCMV) IE1 or M84, a similar level of protection against MCMV infection was achieved. However, the percentage of antigen-specific CD8+ T cells elicited by IE1 was higher than that by M84 as measured by intracellular cytokine staining when splenocytes were stimulated with an epitope peptide (M. Ye at al., J. Virol. 76:2100-2112, 2002). We show here that after DNA vaccination with M84, a higher percentage of M84-specific CD8+ T cells was detected when splenocytes were stimulated with J774 cells expressing full-length M84. When the defined M84 epitope 297-305 was deleted, the mutant DNA vaccine was still protective against MCMV replication and induced strong M84-specific CD8+-T-cell responses. The M84 gene was subsequently subcloned into three fragments encoding overlapping protein fragments. When mice were immunized with each of the M84 subfragment DNAs, at least two additional protective CD8+-T-cell epitopes were detected. In contrast to strong responses after DNA vaccination, M84-specific CD8+-T-cell responses were poorly induced during MCMV infection. The weak M84-specific response after MCMV infection was not due to poor antigen presentation in antigen-presenting cells, since both J774 macrophages and primary peritoneal macrophages infected with MCMV in vitro were able to efficiently and constitutively present M84-specific epitopes starting at the early phase of infection. These results indicate that antigen presentation by macrophages is not sufficient for M84-specific CD8+-T-cell responses during MCMV infection.

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Strong CD8 T-Cell Responses following Coimmunization with Plasmids Expressing the Dominant pp89 and Subdominant M84 Antigens of Murine Cytomegalovirus Correlate with Long-Term Protection against Subsequent Viral Challenge

Journal of Virology ◽

10.1128/jvi.76.5.2100-2112.2002 ◽

2002 ◽

Vol 76 (5) ◽

pp. 2100-2112 ◽

Cited By ~ 30

Author(s):

Ming Ye ◽

Christopher S. Morello ◽

Deborah H. Spector

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

T Cell Responses ◽

T Cell Response ◽

Murine Cytomegalovirus ◽

Dna Immunization ◽

Mcmv Infection ◽

Viral Challenge ◽

Cell Responses

ABSTRACT We previously showed that intradermal immunization with plasmids expressing the murine cytomegalovirus (MCMV) protein IE1-pp89 or M84 protects against viral challenge and that coimmunization has a synergistic protective effect (C. S. Morello, L. D. Cranmer, and D. H. Spector, J. Virol. 74:3696-3708, 2000). Using an intracellular gamma interferon cytokine staining assay, we have now characterized the CD8+ T-cell response after DNA immunization with pp89, M84, or pp89 plus M84. The pp89- and M84-specific CD8+ T-cell responses peaked rapidly after three immunizations. DNA immunization and MCMV infection generated similar levels of pp89-specific CD8+ T cells. In contrast, a significantly higher level of M84-specific CD8+ T cells was elicited by DNA immunization than by MCMV infection. Fusion of ubiquitin to pp89 enhanced the CD8+ T-cell response only under conditions where vaccination was suboptimal. Three immunizations with either pp89, M84, or pp89 plus M84 DNA also provided significant protection against MCMV infection for at least 6 months, with the best protection produced by coimmunization. A substantial percentage of antigen-specific CD8+ T cells remained detectable, and they responded rapidly to the MCMV challenge. These results underscore the importance of considering antigens that do not appear to be highly immunogenic during infection as DNA vaccine candidates.

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DNA Immunization Using Highly Conserved Murine Cytomegalovirus Genes Encoding Homologs of Human Cytomegalovirus UL54 (DNA Polymerase) and UL105 (Helicase) Elicits Strong CD8 T-Cell Responses and Is Protective against Systemic Challenge

Journal of Virology ◽

10.1128/jvi.00633-07 ◽

2007 ◽

Vol 81 (14) ◽

pp. 7766-7775 ◽

Cited By ~ 21

Author(s):

Christopher S. Morello ◽

Laura A. Kelley ◽

Michael W. Munks ◽

Ann B. Hill ◽

Deborah H. Spector

Keyword(s):

T Cells ◽

T Cell ◽

Dna Polymerase ◽

Human Cytomegalovirus ◽

Cd8 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Murine Cytomegalovirus ◽

Dna Immunization ◽

Cell Responses

ABSTRACT Human cytomegalovirus (HCMV) establishes a lifelong infection with the potential for reinfection or viral transmission even in the presence of strong and diverse CD8 T-lymphocyte responses. This suggests that the CMVs skew the host T-cell response in order to favor viral persistence. In this study, we hypothesized that the essential, nonstructural proteins that are highly conserved among the CMVs may represent a novel class of T-cell targets for vaccine-mediated protection due to their requirements for expression and sequence stability, but that the observed subdominance of these antigens in the CMV-infected host results from the virus limiting the T-cell responses to otherwise-protective specificities. We found that DNA immunization of mice with the murine CMV (MCMV) homologs of HCMV DNA polymerase (M54) or helicase (M105) was protective against virus replication in the spleen following systemic challenge, with the protection level elicited by the M54 DNA being comparable to that of DNA expressing the immunodominant IE1 (pp89). Intracellular gamma interferon staining of CD8 T cells from mice immunized with either the M54 or M105 DNAs showed strong primary responses that recalled rapidly after viral challenge. M54- and M105-specific CD8 T cells were detected after the primary MCMV infection, but their levels were not consistently above the background level. The conserved, essential proteins of the CMVs thus represent a novel class of CD8 T-cell targets that may contribute to a successful HCMV vaccine strategy.

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Obesity results in higher PD-1-mediated T-cell suppression but greater T-cell effector functions following blockade.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.65 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 65-65 ◽

Cited By ~ 2

Author(s):

Robert J. Canter ◽

Ethan Aguilar ◽

Ziming Wang ◽

Catherine Le ◽

Lam Khuat ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Responses ◽

Murine Cytomegalovirus ◽

Obese Mice ◽

Effector Functions ◽

Cell Responses ◽

The Central Nervous System ◽

The Impact ◽

Cell Effector

65 Background: Obesity is increasingly prevalent and viewed as a critical co-factor in many pathologic conditions due to metabolic, inflammatory and immune perturbations. We performed a multi-species evaluation of the impact of obesity T cell effector functions and markers of immune exhaustion. Methods: We examined the impact of obesity on PD-1 and T cell-mediated responses across different pre-clinical models (tumor, infection, and autoimmune encephalomyelitis [EAE]) and species (mouse, dog, non-human primate, and human). Results: CD4 and CD8 T cells from obese mice, dogs, non-human primates and humans displayed increases in memory T cells and PD-1 expression, as well as impaired proliferative responses compared to lean controls, indicating a greater degree of T cell exhaustion at baseline. Following immunization with myelin oligodendrocyte glycoprotein, obese mice were resistant to induction of EAE, correlating with reduced antigen-specific CD4 T cells in the central nervous system. Administration of anti-PD-1 resulted in restoration of EAE and increased antigen-specific T cell numbers in obese mice. Tumors in obese mice exhibited accelerated growth compared to lean mice, and T cells displayed higher PD-1 expression correlating with RNAseq/molecular signatures of exhaustion compared to tumor-bearing lean mice. PD-1 blockade resulted in marked anti-tumor effects only in obese mice, and not lean. Impaired viral resistance to murine cytomegalovirus (MCMV) resulted was seen in obese mice, associated with increased PD-1/PD-L1 expression, which was reversible by PD-1/PD-L1 blockade. Conclusions: Obesity results in an increase in PD-1/PD-L1 expression and inhibition of T cell responses across species, and blockade not only reverses this inhibition but also leads to markedly augmented T cell effector responses compared to lean counterparts where no effects were observed. These results highlight how the immune system has evolved to control T cell responses using checkpoints contingent on dynamic host conditions and have translational relevance for predicting both efficacy and toxicity in clinical immuno-oncology.

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The Early Kinetics of Cytomegalovirus-Specific CD8+ T-Cell Responses Are Not Affected by Antigen Load or the Absence of Perforin or Gamma Interferon

Journal of Virology ◽

10.1128/jvi.02127-07 ◽

2008 ◽

Vol 82 (10) ◽

pp. 4931-4937 ◽

Cited By ~ 17

Author(s):

Daniel M. Andrews ◽

Christopher E. Andoniou ◽

Peter Fleming ◽

Mark J. Smyth ◽

Mariapia A. Degli-Esposti

Keyword(s):

T Cells ◽

T Cell ◽

Cell Expansion ◽

T Cell Responses ◽

Gamma Interferon ◽

Murine Cytomegalovirus ◽

Cell Responses ◽

Ifn Γ ◽

T Cell Expansion ◽

Kinetics Of

ABSTRACT Both innate and adaptive immune responses participate in the control of murine cytomegalovirus (mCMV) infection. In some mouse strains, like BALB/c, the control of infection relies on the activities of CD8+ T cells. mCMV-specific CD8+ T-cell responses are unusual in that, even after mCMV has been controlled in the periphery, the numbers of circulating virus-specific CD8+ T cells remain high compared to those observed in other viral infections. To better understand the generation and maintenance of mCMV-specific CD8+ T-cell responses, we evaluated how antigen load and effector molecules, such as perforin (Prf) and gamma interferon (IFN-γ), influence these responses during acute infection in vivo. Viral burden affected the magnitude, but not the early kinetics, of antigen-specific CD8+ T-cell responses. Similarly, the magnitude of virus-specific CD8+ T-cell expansion was affected by Prf and IFN-γ, but contraction of antigen-specific responses occurred normally in both Prf- and IFN-γ-deficient mice. These data indicate that control of mCMV-specific CD8+ T-cell expansion and contraction is more complex than anticipated and, despite the role of Prf or IFN-γ in controlling viral replication, a full program of T-cell expansion and contraction can occur in their absence.

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Conditional silencing of H-2Dbclass I molecule expression on dendritic cells modulates the protective and pathogenic kinetics of virus-antigen specific CD8 T cell responses during Theiler’s Virus infection

10.1101/632265 ◽

2019 ◽

Author(s):

Zachariah P. Tritz ◽

Robin C. Orozco ◽

Courtney S. Malo ◽

Lila T Yokanovich ◽

Katayoun Ayasoufi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antigen Presentation ◽

Mhc Class I ◽

Cd8 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Class I ◽

Viral Control ◽

Cell Responses

ABSTRACTTheiler’s murine encephalomyelitis virus (TMEV) infection of the central nervous system is rapidly cleared in C57BL/6 mice by an anti-viral CD8 T cell response restricted by the MHC class I molecule, H-2Db. While the CD8 T cell response against neurotropic viruses is well characterized, the identity and function of the antigen presenting cell(s) involved in this process is(are) less well defined. To address this gap in knowledge, we developed a novel C57BL/6 H-2Dbconditional knockout mouse that expresses an H-2Dbtransgene in which the transmembrane domain locus is flanked by LoxP sites. We crossed these H-2DbLoxP mice with MHC class I-deficient mice expressing Cre-recombinase under either the CD11c or LysM promoter in order to silence H-2Dbrestricted antigen presentation predominantly in dendritic cells or macrophages, respectively. Upon challenge with intracranial TMEV infection, we observe that CD11c+ APCs are critical for early priming of CD8 T cells against the immunodominant TMEV peptide VP2121-130 presented in the context of the H-2Dbmolecule. This stands in stark contrast to later time points post TMEV infection where CD11c+ APCs appear dispensable for the activation of antigen-specific T cells; the functionality of these late-arising antiviral CD8 T cells is reflected in the restoration of viral control at later time points. These late-arising CD8 T cells also retain their capacity to induce blood-brain barrier disruption. In contrast, when H-2Dbrestricted antigen presentation was selectively silenced in LysM+ APCs there was no overt impact on the priming of Db:VP2121-130 epitope-specific CD8 T cells, although a modest reduction in immune cell entry into the CNS was observed. This work establishes a model system which enables critical dissection of MHC class I restricted antigen presentation to T cells, revealing cell specific and temporal features involved in the generation of antiviral CD8 T cell responses. Employing this novel system, we established CD11c+ cells as a pivotal driver of acute, but not later-arising, antiviral CD8 T cell responses against the TMEV immunodominant epitope VP2121-130, with functional implications both for T cell-mediated viral control and immunopathology.

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Intrahepatic Cross-Presentation and Hepatocellular Antigen Presentation Play Distinct Roles in the Induction of Hepatitis B Virus-Specific CD8+T Cell Responses

Journal of Virology ◽

10.1128/jvi.00920-18 ◽

2018 ◽

Vol 92 (21) ◽

Cited By ~ 7

Author(s):

Yasuhiro Murata ◽

Keigo Kawashima ◽

Knvul Sheikh ◽

Yasuhito Tanaka ◽

Masanori Isogawa

Keyword(s):

T Cells ◽

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Antigen Presentation ◽

Hematopoietic Cells ◽

T Cell Responses ◽

Cross Presentation ◽

Cell Responses ◽

B Virus

ABSTRACTCD8+T cells are the key cellular effectors mediating the clearance of hepatitis B virus (HBV) infections. However, early immunological events surrounding the priming of HBV-specific CD8+T cell responses remain poorly understood. This study examined the importance of priming location and the relative contribution of endogenous antigen presentation by hepatocytes versus cross-presentation by bone marrow-derived cells to the induction of functional HBV-specific CD8+T cell responses using the animal models of acute and chronic HBV infection. Functional HBV-specific CD8+T cell responses could be induced to intrahepatically expressed HBV even when T cell homing to the lymphoid tissues was severely suppressed, suggesting that functional priming could occur in the liver. The expansion of HBV-specific CD8+T cells was significantly reduced in the mice whose major histocompatibility complex (MHC) class I expression was mostly restricted to nonhematopoietic cells, suggesting the importance of cross-presentation by hematopoietic cells in the induction of HBV-specific CD8+T cells. Strikingly, the expansion and cytolytic differentiation of HBV-specific CD8+T cells were reduced even more severely in the mice whose MHC class I expression was restricted to hematopoietic cells. Collectively, these results indicate that cross-presentation is required but relatively inefficient in terms of inducing the cytolytic differentiation of HBV-specific CD8+T cells by itself. Instead, the expansion and functional differentiation of HBV-specific CD8+T cells are primarily dependent on hepatocellular antigen presentation.IMPORTANCEHepatitis B virus (HBV) causes acute and chronic hepatitis. Approximately 260 million people are chronically infected with HBV and under an increased risk of developing cirrhosis and hepatocellular carcinoma. Host immune responses, particularly HBV-specific CD8+T cell responses, largely determine the outcome of HBV infection. It is widely accepted that antigen inexperienced CD8+T cells should be initially activated by professional antigen-presenting cells (pAPCs) in lymphoid tissues to differentiate into effector CD8+T cells. However, this notion has not been tested for HBV-specific CD8+T cells. In this study, we show that HBV-specific CD8+T cell responses can be induced in the liver. Surprisingly, antigen presentation by hepatocytes is more important than cross-presentation by hematopoietic cells for the induction of HBV-specific CD8+T cell responses. These results revealed a previously unappreciated role of antigen presentation by hepatocytes in the induction of HBV-specific CD8+T cell responses.

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Direct Priming of CD8+ T Cells Persists in the Face of Cowpox Virus Inhibitors of Antigen Presentation

Journal of Virology ◽

10.1128/jvi.00186-21 ◽

2021 ◽

Author(s):

Leon C.W. Lin ◽

Sarah N. Croft ◽

Nathan P. Croft ◽

Yik Chun Wong ◽

Stewart A. Smith ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antigen Presentation ◽

T Cell Responses ◽

Cowpox Virus ◽

Viral Immunity ◽

Cell Responses ◽

Infected Cells ◽

The Impact ◽

Viral Inhibitors

Vaccinia virus (VACV) was the vaccine used to eradicate smallpox and is being repurposed as a vaccine vector. CD8+ T cells are key anti-viral mediators, but require priming to become effector or memory cells. Priming requires an interaction with dendritic cells that are either infected (direct priming), or that have acquired virus proteins but remain uninfected (cross priming). To investigate CD8+ T cell priming pathways for VACV, we engineered the virus to express CPXV12 and CPXV203, two inhibitors of antigen presentation encoded by cowpox virus. These intracellular proteins would be expected to block direct but not cross priming. The inhibitors had diverse impacts on the size of anti-VACV CD8+ T cell responses across epitopes and by different infection routes in mice, superficially suggesting variable use of direct and cross priming. However, when we then tested a form of antigen that requires direct priming, we found surprisingly that CD8+ T cell responses were not diminished by co-expression with CPXV12 and CPXV203. We then directly quantified the impact of CPXV12 and CPXV203 on viral antigen presentation using mass spectrometry, which revealed strong, but incomplete inhibition of antigen presentation by the CPXV proteins. Therefore, direct priming of CD8+ T cells by poxviruses is robust enough to withstand highly potent viral inhibitors of antigen presentation. This is a reminder of the limits of viral immune evasion and shows that viral inhibitors of antigen presentation cannot be assumed to dissect cleanly direct and cross priming of anti-viral CD8+ T cells. Importance CD8+ T cells are key to anti-viral immunity, so it is important to understand how they are activated. Many viruses have proteins that protect infected cells from T cell attack by interfering with the process that allows virus infection to be recognised by CD8+ T cells. It is thought that these proteins would also stop infected cells from activating T cells in the first place. However, we show here that this is not the case for two very powerful inhibitory proteins from cowpox virus. This demonstrates the flexibility and robustness of immune processes that turn on the immune responses required to fight infection.

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The Fates of Dendritic Cells and Antigen Regulate CD4+ T Cell Responses

10.26686/wgtn.16973662.v1 ◽

2021 ◽

Author(s):

◽

Joel Zhi-Iong Ma

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Antigen Presentation ◽

T Cell Responses ◽

Effector T Cells ◽

T Cell Proliferation ◽

Cell Responses ◽

Antigen Transfer ◽

Antigen Presenting

<p>The rapid activation of effector T cells by antigen-presenting dendritic cells (DCs) is necessary to contain and eradicate pathogens. Upon eradication of the pathogens by effector T cells, the immune response eventually resolves, and the clearance of residual antigen is necessary to prevent immune cell exhaustion or immunopathology. It has been proposed that the elimination of antigen-presenting DCs by CD8+ cytotoxic T cells (CTLs) limits the duration of antigen presentation, hence resolving ongoing immune responses. However, inter-DC antigen transfer spreads antigens for further antigen presentation and may reduce the effect of CTL-mediated DC killing. The aim of my thesis was to examine the impact of CTL-mediated DC killing and inter-DC antigen transfer on the induction and the quality of resulting T cell responses. Initial experiments established that CTLs eliminated antigen-bearing DCs mainly through the cytolytic molecule perforin, whereas FasL played a minor role. CTL-mediated DC killing prevented antigen-bearing DCs from stimulating naive CD4+ and CD8+ T cells in the draining lymph nodes. Thus, CTLs regulated the clonal expansion of naive T cells by controlling the survival of antigen-presenting DCs. The efficiency of CTL-mediated DC killing depended on the method of antigen loading onto DCs, and to a lesser extent, the method of generating CTLs. Surprisingly, efficient CTL-mediated DC killing that completely prevented the accumulation of injected DCs in the lymph nodes did not abolish T cell proliferation, indicating that other antigen presenting cells (APCs) were inducing the residual T cell proliferation when the antigen-bearing DCs were eliminated by CTLs. Further investigations revealed that the antigen from the injected DCs was transferred to host DCs. In the absence of direct antigen presentation by injected DCs, host DCs stimulated local T cell proliferation but did not induce a systemic effector T cell response. In contrast, in the presence of efficient CTL-mediated DC killing, inter-DC antigen transfer enabled the host DCs to stimulate T cell proliferation. These T cells then developed into iii functional effector T cells. In conclusion, in the absence of inter-DC antigen transfer, CTLmediated DC killing reduces the size of T cell responses. However, in the presence of inter- DC antigen transfer, the impact of CTL-mediated DC killing is reduced, hence influencing the size and quality of T cell responses. My findings shed light on how CTL-mediated DC killing and inter-DC antigen transfer regulate immune responses and how DC vaccine regimens for immunotherapy can be improved.</p>

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The Fates of Dendritic Cells and Antigen Regulate CD4+ T Cell Responses

10.26686/wgtn.16973662 ◽

2021 ◽

Author(s):

◽

Joel Zhi-Iong Ma

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Antigen Presentation ◽

T Cell Responses ◽

Effector T Cells ◽

T Cell Proliferation ◽

Cell Responses ◽

Antigen Transfer ◽

Antigen Presenting

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P06.05 Endogenous T-cell responses to ten major cancer testis antigens are frequent in esophago-gastric adenocarcinoma and antigen-specific T cells can be expanded using CD40-activated B cells

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-itoc8.39 ◽

2021 ◽

Vol 9 (Suppl 1) ◽

pp. A21.1-A21

Author(s):

M Thelen ◽

M Garcia-Marquez ◽

J Lehmann ◽

D Keller ◽

E Preugszat ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Antigen Presentation ◽

T Cell Responses ◽

Cell Abundance ◽

Cell Responses ◽

Cancer Testis Antigens ◽

Cancer Testis ◽

Activated B Cells

BackgroundTumor-associated antigens (TAAs) and especially cancer testis antigens (CTAs) are classical tumor-specific targets for immunotherapies. As TAAs are shared between patients, strategies aiming to exploit these targets are scalable and potentially applicable across different types of cancer. Loss of target antigens and other mechanisms of immune escape have limited the success of CTA-directed immunotherapy. CAR T cells and other highly effective cellular therapies have renewed the interest in TAAs. Especially combined targeting of multiple antigens appears highly promising as recently shown in lymphoma. In our study, we aimed to characterize CTA-expression patterns and their impact on endogenous T-cell responses, T-cell abundance and antigen-presentation in esophago-gastric adenocarcinoma (EGA).Materials and Methods41 treatment-naïve EGA patients were included in our study. RNA of tumor and patient-matched healthy tissue was isolated and used for NanoString based RNA expression analysis of 26 CTAs and 25 genes associated with antigen-presentation. Based on CTA expression, 10 peptide pools were selected and co-cultured with peripheral blood mononuclear cells (PBMCs, n=21) to determine cellular anti-tumor immune responses in a FluoroSpot assay. T-cell abundance was assessed using immunohistochemistry (CD3, CD8) and digital image analyses of tumor area and invasive margin. Autologous CD40 activated B cells were used to expand antigen-specific T cells using peptide pools of CTAs.ResultsNanoString analysis revealed pronounced differences regarding CTA expression, with CEP55 and MAGEA3/6 showing strong expression, while NY-ESO-1 or MAGEA1 were only weakly expressed. 68.3% (28/41) of the patients showed expression of ≥ 5/10 analyzed TAAs simultaneously. In line with the frequent expression, 75.0% of the patients showed a cellular response against at least one of the TAAs. T-cell responses were most frequently detected to Survivin and NY-ESO-1 (65.0% and 52.6% of patients, respectively), while only 20.0% responded to CEP55 or TTK peptide pools. Overall, 6/20 patients showed cellular responses against ≥5 TAAs simultaneously. We found a strong correlation of T-cell abundance and antigen-presentation. In addition, patients with a high Immune-Score showed increased TAA expression. Finally, we demonstrate feasibility of TAA-specific T-cell expansion using CD40 activated B cells as potential strategy to induce or enhance TAA immune responses in EGA.ConclusionsOur study highlights the importance of TAAs in EGA. The identified antigens are highly relevant for immunomonitoring of clinical trials and as targets for immunotherapy. Personalized immunotherapeutic strategies targeting EGA-specific or even patient specific TAAs appear highly promising in this challenging disease.Disclosure InformationM. Thelen: None. M. Garcia-Marquez: None. J. Lehmann: None. D. Keller: None. E. Preugszat: None. M. von Bergwelt-Baildon: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Astellas, Roche, MSD. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Modest; BMS. F. Consultant/Advisory Board; Modest; BMS. H.A. Schlößer: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Astra Zeneca.

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