Cytomegalovirus vector expressing RAE‐1γ induces enhanced anti‐tumor capacity of murine CD8<sup>+</sup> T cells

Tršan, Tihana; Vuković, Kristina; Filipović, Petra; Brizić, Ana Lesac; Lemmermann, Niels A. W.; Schober, Kilian; Busch, Dirk H.; Britt, William J.; Messerle, Martin; Krmpotić, Astrid; Jonjić, Stipan

doi:10.1002/eji.201746964

Cited by 20 publications

(33 citation statements)

References 53 publications

(77 reference statements)

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“…However, additional approaches will be necessary to develop a HCMV vaccine which will be efficient against congenital infection. We have already shown in MCMV model that by exploiting viral immunoevasins one can generate highly attenuated vaccine vectors which are at the same time able to induce potent cellular immunity (Slavuljica et al, 2010, Trsan et al, 2013, Trsan et al, 2017). One important question that remains unanswered is whether CMV evades the development of more efficient antibody response.…”

Section: Discussionmentioning

confidence: 99%

Brain‐resident memory CD8⁺ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

et al. 2018

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Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with mouse cytomegalovirus (MCMV) intraperitoneally is a well-established model of congenital human cytomegalovirus infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here, we used this model to investigate the role, dynamics, and phenotype of CD8 T cells in the brain following infection of newborn mice. We show that CD8 T cells infiltrate the brain and form a pool of tissue-resident memory T cells (T cells) that persist for lifetime. Adoptively transferred virus-specific CD8 T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology, and remain in the brain as T cells. Brain CD8 T cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8 T cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain.

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Section: Discussionmentioning

confidence: 99%

Brain‐resident memory CD8⁺ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

et al. 2018

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“…CD8 to considered as glycoprotein heterodimer made up of alpha and beta chains covalently linked by a disulfide bond. The function of CD8 is to bind to a major histocompatibility complex class I molecule associated with the T cell receptor and stimulate its cytotoxic effect on cancer cells and induce a vital role in cell-mediated immunity [ 23 ]. Although many studies have shown patients with higher intra-tumor CD8 + TILs have superior survival in many malignancies [ 24 – 26 ], there was no significant difference in prognosis observed within our study probably due to the limited sample size used.…”

Section: Discussionmentioning

confidence: 99%

CD25 and TGF-β blockade based on predictive integrated immune ratio inhibits tumor growth in pancreatic cancer

Zhao

Yin

et al. 2018

J Transl Med

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BackgroundThe prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor due to the difficulty of disease diagnosis and therapy. Immunotherapy has had robust performance against several malignancies, including PDAC. In this study, we aim to analyze the expression of CD8 and FoxP3 on T lymphocytes and TGF-β expression in tumor tissues, and then analyze the possible clinical significance of these finding in order to find a novel effective immunotherapy target in PDAC using a murine model.MethodsA tissue microarray using patient PDAC samples was stained and analyzed for associations with clinicopathological characteristics. A preclinical murine model administrated with various immunotherapies were analyzed by growth inhibitor, flow cytometry, enzyme-linked immuno sorbent assay and immunohistochemistry.ResultsThe infiltrating FoxP3+ regulatory T cells (Tregs) in tumor tissues were associated with survival, while CD8+ tumor infiltrating lymphocytes (TILs) were not. Considering the drawbacks of these measure alone, the number of CD8+ and FoxP3+ T cells were combined to create a new estimated value—integrated immune ratio (IIR), which showed excellent validity in survival risk stratification. IIR was further verified as an independent prognostic factor according to multivariate analysis as well as TGF-β expression. Association between TGF-β expression and infiltrating Tregs was also verified. Then, in our preclinical murine model, CD25 and TGF-β combination blockade had a higher tumor growth inhibitor value. This combination therapy significantly depleted periphery and intra-tumor FoxP3+ Tregs while increasing intra-tumor CD8+ TILs levels compared to controls or anti-TGF-β monotherapy (p < 0.05). Anti-CD25 monotherapy alone also had the ability to deplete periphery and intra-tumor Tregs (p < 0.05). The excretion of intra-tumor IL-10, TGF-β was notably lower but higher IFN-γ excretion in this combination immunotherapy. Such combination immunotherapy was further confirmed to synergize with anti-PD-1 monotherapy to improve tumor growth inhibition and cure rates.ConclusionsThe combination of CD25, TGF-β and PD-1 blockade plays a potentially effective role in inhibiting tumor formation and progression. Our results also provide a strong rational strategy for use of IIR in future immunotherapy clinical trials.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1673-6) contains supplementary material, which is available to authorized users.

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“…Unexpectedly, this response was also preserved in NKG2D −/− mice, suggesting an NKG2D-independent immune function of RAE-1γ [28]. Consequently, a RAE-1γMCMV vector expressing the SIINFEKL epitope induced a robust CD8 T cell response able to contain the growth of an OVA-expressing tumour in prophylactic and therapeutic settings [48]. Therapeutic RAE-1γMCMV vaccination was further enhanced by blocking the immune checkpoints TIGIT and PD-1, supporting a synergistic role with tumour immunotherapy.…”

Section: Innate Immune Response To CMV Is Relevant For Its Vector Promentioning

confidence: 90%

“…Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Interestingly, a replication-deficient MCMV carrying an attenuating mutation within the DNA primase gene, while able to induce primary T cell responses could not replicate the characteristic MI CD8 response [49].…”

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confidence: 99%

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

2019

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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.Vaccines 2019, 7, 152 2 of 28 CMV-based vaccines, the large pool of functional antigen-specific T cells in the periphery and the possibility to modify CMV genomes due to improvements in viral genetics [11] draw a strong interest to CMV as a vaccine vector [12,13] (Table 1). The inflationary response appears linked to immune protection [14,15] and has been proposed as a target for immunization induction [16]. Vaccines 2019, 7, 152 3 of 28 Full-length HPV16 E6 and E7 Antigen fused to the C-terminus of ie2 Transient limitation of tumour cell growth MCMV IE2E7 [14] MHC-I restricted HPV16 E7 49-57 epitope Epitope fused to the C-terminus of ie2 No tumour cell growth upon challenge MCMV-M79-FKBP-E7 [36] MCMV Smith Strain with FKBP-mediated destabilization of the essential M79 gene Vaccines 2019, 7, 152 5 of 28Besides the exceptional induction of adaptive immune response in humans [2,37], CMV possesses assets that conveniently address weaknesses common to other vector candidates. The cloning of CMV genomes as bacterial artificial chromosomes in Escherichia coli [38] has allowed genetic engineering approaches to effectively express multiple exogenous immunogens or modify large genome portions [39,40]. Furthermore, CMV is known to superinfect hosts with a history of prior exposure to the virus [41] due to its immune evasive properties that protect the virus from recognition by primed T-cells [42] and CMV vectors induce protective immunity in experimentally vaccinated animals with documented prior exposure to 36]. Therefore, CMV vector candidates would avoid immune interference as described for AdV. CMV is a pathogenic organism in immunodeficient populations [43] or in congenitally infected children. Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Inter...

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Cytomegalovirus vector expressing RAE‐1γ induces enhanced anti‐tumor capacity of murine CD8⁺ T cells

Cited by 20 publications

References 53 publications

Brain‐resident memory CD8⁺ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

Brain‐resident memory CD8⁺ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

CD25 and TGF-β blockade based on predictive integrated immune ratio inhibits tumor growth in pancreatic cancer

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

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Cytomegalovirus vector expressing RAE‐1γ induces enhanced anti‐tumor capacity of murine CD8+ T cells

Cited by 20 publications

References 53 publications

Brain‐resident memory CD8+ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

Brain‐resident memory CD8+ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

CD25 and TGF-β blockade based on predictive integrated immune ratio inhibits tumor growth in pancreatic cancer

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

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Product

Resources

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Cytomegalovirus vector expressing RAE‐1γ induces enhanced anti‐tumor capacity of murine CD8⁺ T cells

Brain‐resident memory CD8⁺ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

Brain‐resident memory CD8⁺ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation