T Cell Co-Stimulation: Inhibition of Immunosuppression?

Sundqvist, Kristina

doi:10.3389/fimmu.2018.00974

Cited by 8 publications

(13 citation statements)

References 50 publications

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“…PF4‐CXCR3 ligation is accountable in the present observations because both CXCR3 blockade by its inhibitor AMG487 and CXCR3 knock‐down by siRNAs diminished rhPF4‐ or markedly attenuated platelet‐enhanced T effector cell responses. Other PF4 receptors are of functionally less importance in the present setting, because GAG and αV are considered as co‐receptors, 33 while LRP1 and Mac1/CD11b are poorly expressed on T cells 36 . Notably, PF4‐CXCR3 ligation attenuated Akt phosphorylation/activity.…”

Section: Discussionmentioning

confidence: 95%

Platelet factor 4 enhances CD4+ T effector memory cell responses via Akt‐PGC1α‐TFAM signaling‐mediated mitochondrial biogenesis

Tan

Gisterå

et al. 2020

Journal of Thrombosis and Haemostasis

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Section: Discussionmentioning

confidence: 95%

Platelet factor 4 enhances CD4+ T effector memory cell responses via Akt‐PGC1α‐TFAM signaling‐mediated mitochondrial biogenesis

Tan

Gisterå

et al. 2020

Journal of Thrombosis and Haemostasis

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“…This is still well below the strong response we observed with targeted mRNA-LNPs at all tested doses and is likely due to expression of an ApoE receptor by some T cells. 28 , 29 While administration of 90 μg of anti-CD4/Cre mRNA-LNPs resulted in an even higher percentage of ZsGreen1 + CD4 + T cells (not shown), this amount of LNPs proved to be toxic in all groups (both unconjugated and control IgG-conjugated, and CD4-targeted LNP treatments); thus, we eliminated that dose from further experiments. This was not a surprise, since cationic lipids are well known to cause toxicity at high doses.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the signal from non-targeted mRNA-LNPs in both splenic and lymphatic tissues at high dose (30 μg per mouse) was not zero, as observed in untreated mice. This observation is likely due to expression of an ApoE receptor by certain T cells, 28 , 29 as LNPs bind ApoE and typically target the liver. 38 We could further increase the percentage of gene-edited cells by multiple injections of anti-CD4/mRNA-LNPs.…”

Section: Discussionmentioning

confidence: 99%

Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs

et al. 2021

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Nucleoside-modified messenger RNA (mRNA)-lipid nanoparticles (LNPs) are the basis for the first two EUA (Emergency Use Authorization) COVID-19 vaccines. The use of nucleoside-modified mRNA as a pharmacological agent opens immense opportunities for therapeutic, prophylactic and diagnostic molecular interventions. In particular, mRNA-based drugs may specifically modulate immune cells, such as T lymphocytes, for immunotherapy of oncologic, infectious and other conditions. The key challenge, however, is that T cells are notoriously resistant to transfection by exogenous mRNA. Here, we report that conjugating CD4 antibody to LNPs enables specific targeting and mRNA interventions to CD4+ cells, including T cells. After systemic injection in mice, CD4-targeted radiolabeled mRNA-LNPs accumulated in spleen, providing $30-fold higher signal of reporter mRNA in T cells isolated from spleen as compared with nontargeted mRNA-LNPs. Intravenous injection of CD4-targeted LNPs loaded with Cre recombinase-encoding mRNA provided specific dose-dependent loxP-mediated genetic recombination, resulting in reporter gene expression in about 60% and 40% of CD4+ T cells in spleen and lymph nodes, respectively. T cell phenotyping showed uniform transfection of T cell subpopulations, with no variability in uptake of CD4-targeted mRNA-LNPs in naive, central memory, and effector cells. The specific and efficient targeting and transfection of mRNA to T cells established in this study provides a platform technology for immunotherapy of devastating conditions and HIV cure.

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“…In addition, DC maturation can also be hindered by the lack of promaturation signals. In the absence of sufficient costimulatory signals on the surface of DCs, antigen presentation can result in the generation of immunosuppressive T cells or incompetent T cells ( 57 , 72 ). Therefore, designing hydrogels with powerful DC recruitment abilities plays an important role in stimulating the downstream immune response.…”

Section: Strategies For Hydrogel-based Cancer Vaccine To Initiate An ...mentioning

confidence: 99%

“…4B ) ( 70 ). The lack of the costimulatory signals in T cell activation might promote the development of regulatory T cells that is related to immunosuppression ( 72 ). Therefore, designing hydrogels loaded with multiple signal molecules to specifically activate CTLs is necessary to enhance the CTL-induced immune response and alleviate immunosuppression.…”

Section: Strategies For Hydrogel-based Cancer Vaccine To Initiate An ...mentioning

confidence: 99%

Hydrogel-guided strategies to stimulate an effective immune response for vaccine-based cancer immunotherapy

et al. 2022

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Cancer vaccines have attracted widespread interest in tumor therapy because of the potential to induce an effective antitumor immune response. However, many challenges including weak immunogenicity, off-target effects, and immunosuppressive microenvironments have prevented their broad clinical translation. To overcome these difficulties, effective delivery systems have been designed for cancer vaccines. As carriers in cancer vaccine delivery systems, hydrogels have gained substantial attention because they can encapsulate a variety of antigens/immunomodulators and protect them from degradation. This enables hydrogels to simultaneously reverse immunosuppression and stimulate the immune response. Meanwhile, the controlled release properties of hydrogels allow for precise temporal and spatial release of loads in situ to further enhance the immune response of cancer vaccines. Therefore, this review summarizes the classification of cancer vaccines, highlights the strategies of hydrogel-based cancer vaccines, and provides some insights into the future development of hydrogel-based cancer vaccines.

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T Cell Co-Stimulation: Inhibition of Immunosuppression?

Cited by 8 publications

References 50 publications

Platelet factor 4 enhances CD4+ T effector memory cell responses via Akt‐PGC1α‐TFAM signaling‐mediated mitochondrial biogenesis

Platelet factor 4 enhances CD4+ T effector memory cell responses via Akt‐PGC1α‐TFAM signaling‐mediated mitochondrial biogenesis

Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs

Hydrogel-guided strategies to stimulate an effective immune response for vaccine-based cancer immunotherapy

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