Effective Activation of Human Antigen-Presenting Cells and Cytotoxic CD8+ T Cells by a Calcium Phosphate-Based Nanoparticle Vaccine Delivery System

Scheffel, Florian; Knuschke, Torben; Otto, Lucas; Kollenda, Sebastian; Sokolova, Viktoriya; Cosmovici, Christine; Buer, Jan; Timm, Jörg; Epple, Matthias; Westendorf, Astrid M.

doi:10.3390/vaccines8010110

Cited by 21 publications

(14 citation statements)

References 45 publications

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“…A previous study revealed the requirement of CD28 costimulation for the proliferation of exhausted T cells after PD-1-targeted therapy (22). We have recently described that CpG-functionalized CaP NPVs efficiently activate APCs, indicated by increased expression of the costimulatory B7 molecules CD80 and CD86 after in vitro and in vivo stimulation (8,23,24). Interestingly, activation of APCs was still enhanced in the spleen 7 days after immunization, possibly due to endocrine or paracrine effects.…”

Section: Resultsmentioning

confidence: 92%

A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

Knuschke

Kollenda²,

Wenzek

et al. 2021

mBio

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PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection. Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Prevention of inhibitory signals by blocking PD-L1 in combination with therapeutic vaccination with nanoparticles containing the microbial compound CpG and a CD8+ T cell Gag epitope peptide synergistically enhanced functional virus-specific CD8+ T cell responses and improved viral clearance. We characterized the CD8+ T cell populations that were affected by this combination therapy, demonstrating that new effector cells were generated and that exhausted CD8+ T cells were reactivated at the same time. While CD8+ T cells with high PD-1 (PD-1hi) expression turned into a large population of granzyme B-expressing CD8+ T cells after combination therapy, CXCR5-expressing follicular cytotoxic CD8+ T cells also expanded to a high degree. Thus, our study describes a very efficient approach to enhance virus control and may help us to understand the mechanisms of combination immunotherapy reactivating CD8+ T cell immunity. A better understanding of CD8+ T cell immunity during combination therapy will be important for developing efficient checkpoint therapies against chronic viral infections and cancer. IMPORTANCE Despite significant efforts, vaccines are not yet available for every infectious pathogen, and the search for a protective approach to prevent the establishment of chronic infections, i.e., with HIV, continues. Immune checkpoint therapies targeting inhibitory receptors, such as PD-1, have shown impressive results against solid tumors. However, immune checkpoint therapies have not yet been licensed to treat chronic viral infections, since a blockade of inhibitory receptors alone provides only limited benefit, as demonstrated in preclinical models of chronic viral infection. Thus, there is a high interest in the development of potent combination immunotherapies. Here, we tested whether the combination of a PD-L1 blockade and therapeutic vaccination with functionalized nanoparticles is a potent therapy during chronic Friend retrovirus infection. We demonstrate that the combination therapy induced a synergistic reinvigoration of the exhausted virus-specific CD8+ T cell immunity. Taken together, our results provide further information on how to improve PD-1-targeted therapies during chronic viral infection and cancer.

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Section: Resultsmentioning

confidence: 92%

A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

Knuschke

Kollenda²,

Wenzek

et al. 2021

mBio

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“…Single studies on osseous macrophages revealed that CaP-NPs enhanced inflammation by modulating macrophages while osteogenesis was attenuated (26). Other studies could show that CaP-NPs lead to maturation of antigen presenting cells, cytokine secretion and activation of cytotoxic T cells resulting in a strong immune response (9). Natural killer cells (NK cells) are among the first cells to interact with applied nanoparticles as these innate immune cells can act without prior sensitization.…”

Section: Discussionmentioning

confidence: 99%

“…They served as carriers for antibiotics and have been applied for vaccination and immunization against infectious diseases successfully (8). In contrast to other nanoparticle-preparations, CaP-NP can be loaded with various immune activating components at flexible dosages simultaneously, which optimizes and individualizes the immune response (9). Taken up by dendritic cells CaP-NPs were able to induce a strong immunization in vivo and showed efficiency against experimental retroviral infections (10).…”

Section: Introductionmentioning

confidence: 99%

“…Despite obvious relevance for therapeutic applications, interactions between CaP-NPs and different immune effector cells have not been studied intensively in the past. Many studies focused on interactions between CaP-NPs and macrophages, and little, if any, data are available on the interplay of Ca-P NPs with T cells or NK cells (9). As part of the innate immune system, NK cells are likely to be one of the first cells coming into contact with nanoparticles when those are systemically applied.…”

Section: Introductionmentioning

confidence: 99%

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Reactivity of NK Cells Against Ovarian Cancer Cells Is Maintained in the Presence of Calcium Phosphate Nanoparticles

et al. 2022

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Calcium phosphate nanoparticles (CaP-NPs) are biodegradable carriers that can be functionalized with biologically active molecules. As such, they are potential candidates for delivery of therapeutic molecules in cancer therapies. In this context, it is important to explore whether CaP-NPs impair the natural or therapy-induced immune cell activity against cancer cells. Therefore, in this study, we have investigated the effects of different CaP-NPs on the anti-tumor activity of natural killer (NK) cells using different ovarian cancer (OC) cell line models. We explored these interactions in coculture systems consisting of NK cells, OC cells, CaP-NPs, and therapeutic Cetuximab antibodies (anti-EGFR, ADCC-inducing antibody). Our experiments revealed that aggregated CaP-NPs can serve as artificial targets, which activate NK cell degranulation and impair ADCC directed against tumor targets. However, when CaP-NPs were properly dissolved by sonication, they did not cause substantial activation. CaP-NPs with SiO2-SH-shell induced some activation of NK cells that was not observed with polyethyleneimine-coated CaP-NPs. Addition of CaP-NPs to NK killing assays did not impair conjugation of NK with OC and subsequent tumor cytolytic NK degranulation. Therapeutic antibody coupled to functionalized CaP-NPs maintained substantial levels of antibody-dependent cellular cytotoxic activity. Our study provides a cell biological basis for the application of functionalized CaP-NPs in immunologic anti-cancer therapies.

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“…As carriers, CaP nanoparticles can load antigens at different time points through encapsulation during the particle formation or passive adsorption after particle formation [ 45 ]. Compared with soluble Toll-like receptor (TLR) ligands, TLR ligand and viral antigen functionalised CaP nanoparticles are effective in inducing the efficient maturation of human APCs [ 49 ], as indicated by increase in the levels of co-stimulating molecules and the secretion of proinflammatory cytokines, which cause the remarkable expansion of virus-specific T cells. Another similar design confirmed this conclusion in mice [ 50 ].…”

Section: Nanoparticles As Vaccine Adjuvants In Antiviral Infectionmentioning

confidence: 99%

Design and application of nanoparticles as vaccine adjuvants against human corona virus infection

Mao

Chen

Wang

et al. 2021

Journal of Inorganic Biochemistry

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In recent years, some viruses have caused a grave crisis to global public health, especially the human coronavirus. A truly effective vaccine is therefore urgently needed. Vaccines should generally have two features: delivering antigens and modulating immunity. Adjuvants have an unshakable position in the battle against the virus. In addition to the perennial use of aluminium adjuvant, nanoparticles have become the developing adjuvant candidates due to their unique properties. Here we introduce several typical nanoparticles and their antivirus vaccine adjuvant applications. Finally, for the combating of the coronavirus, we propose several design points, hoping to provide ideas for the development of personalized vaccines and adjuvants and accelerate the clinical application of adjuvants.

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Effective Activation of Human Antigen-Presenting Cells and Cytotoxic CD8+ T Cells by a Calcium Phosphate-Based Nanoparticle Vaccine Delivery System

Cited by 21 publications

References 45 publications

A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

Reactivity of NK Cells Against Ovarian Cancer Cells Is Maintained in the Presence of Calcium Phosphate Nanoparticles

Design and application of nanoparticles as vaccine adjuvants against human corona virus infection

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