DNAM-1 promotes inflammation-driven tumor development via enhancing IFN-γ production

Nakamura-Shinya, Yuho; Iguchi-Manaka, Akiko; Murata, Rikito; Satoh, Kaneo; Vo, Anh Van; Kanemaru, Kazumasa; Shibuya, Akira; Shibuya, Kazuko

doi:10.1093/intimm/dxab099

Cited by 2 publications

(1 citation statement)

References 41 publications

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“…Our results show that EV71 infection interferes the TLR4 signaling pathway by inhibiting the MYD88 activation and downstream NF-κB phosphorylation. Furthermore, studies have shown that EV71 infection can suppress the production of various inflammatory factors, such as IL-6 ( Tanaka et al., 2014 ), NLRP3 ( Zhang et al., 2023 ), COX2 ( Gupta et al., 2018 ) and IFN-γ ( Nakamura-Shinya et al., 2022 ), thereby dampening the immune response and these findings are consistent with our results. In addition, we find that EV71 infection also inhibits the p-TBK1/TBK1 protein level to suppress the antiviral innate immune response.…”

Section: Discussionsupporting

confidence: 92%

TLR4 signalling: the key to controlling EV71 replication and inflammatory response

Hao,

Wang,

et al. 2024

Front. Cell. Infect. Microbiol.

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Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by enterovirus 71 (EV71) that frequently affects children, leading to severe infections in some cases. In general, when infection occurs, the body upregulates inflammatory responses to eliminate pathogenic microorganisms to protect the host from infection. However, EV71 may inhibit host’s innate immunity to promote virus infection. At present, it is not fully understood how EV71 hijack the host cells for its own replication. Toll-like receptor 4 (TLR4), a natural immune receptor, historically associated with bacterial endotoxin-induced inflammatory responses. However, it is still unclear whether and how TLR4 is altered during EV71 infection. In this study, we observed a reduction in both TLR4 protein and gene transcript levels in RD, GES-1, and Vero cells following EV71 infection, as detected by RT-qPCR, immunofluorescence staining and western blot. Furthermore, we observed that the TLR4 downstream molecules of MYD88, p-NF-κB p65, p-TBK1 and related inflammatory cytokines were also reduced, suggesting that antiviral innate immune and inflammatory response were suppressed. To determine the impact of TLR4 changes on EV71 infection, we interfered EV71-infected RD cells with TLR4 agonist or inhibitor and the results showed that activation of TLR4 inhibited EV71 replication, while inhibition of TLR4 promote EV71 replication. Besides, EV71 replication was also promoted in TLR4 siRNA-transfected and EV71-infected RD cells. This suggests that down-regulation the expression of TLR4 by EV71 can inhibit host immune defense to promote EV71 self-replication. This novel mechanism may be a strategy for EV71 to evade host immunity.

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Section: Discussionsupporting

confidence: 92%

TLR4 signalling: the key to controlling EV71 replication and inflammatory response

Hao,

Wang,

et al. 2024

Front. Cell. Infect. Microbiol.

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The Nectin family ligands, PVRL2 and PVR, in cancer immunology and immunotherapy

Murakami,

Ganguly

2024

Front. Immunol.

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In recent years, immunotherapy has emerged as a crucial component of cancer treatment. However, its efficacy remains limited across various cancer types, highlighting unmet needs. Poliovirus receptor-related 2 (PVRL2) and Poliovirus receptor (PVR) are members of the Nectin and Nectin-like Molecules family, known for their role as cell-cell adhesion molecules. With the development of immunotherapy, their involvement in tumor immune mechanisms as immune checkpoint factors has garnered significant attention. PVRL2 and PVR are predominantly expressed on tumor cells and antigen-presenting cells, binding to PVRIG and TIGIT, respectively, which are primarily found on T and NK cells, thereby suppressing antitumor immunity. Notably, gynecological cancers such as ovarian and endometrial cancers exhibit high expression levels of PVRL2 and PVR, with similar trends observed in various other solid and hematologic tumors. Targeting these immune checkpoint pathways offers a promising therapeutic avenue, potentially in combination with existing treatments. However, the immunomodulatory mechanism involving these bindings, known as the DNAM-1 axis, is complex, underscoring the importance of understanding it for developing novel therapies. This article comprehensively reviews the immunomodulatory mechanisms centered on PVRL2 and PVR, elucidating their implications for various cancer types.

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DNAM-1 promotes inflammation-driven tumor development via enhancing IFN-γ production

Cited by 2 publications

References 41 publications

TLR4 signalling: the key to controlling EV71 replication and inflammatory response

TLR4 signalling: the key to controlling EV71 replication and inflammatory response

The Nectin family ligands, PVRL2 and PVR, in cancer immunology and immunotherapy

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