Coming of Age: CD96 Emerges as Modulator of Immune Responses

Georgiev, Hristo; Ravens, Inga; Papadogianni, Georgia; Bernhardt, Günter

doi:10.3389/fimmu.2018.01072

Cited by 93 publications

(92 citation statements)

References 90 publications

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“…CD226 is a costimulatory adhesion molecule expressed by T cells and NK cells. [75][76][77] CD155, expressed on transformed cells, 75 76 can engage CD226. CD96 and TIGIT are on August 5, 2020 by guest.…”

Section: Open Accessmentioning

confidence: 99%

Lifting the innate immune barriers to antitumor immunity

Rothlin

Ghosh

2020

J Immunother Cancer

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The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.

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Section: Open Accessmentioning

confidence: 99%

Lifting the innate immune barriers to antitumor immunity

Rothlin

Ghosh

2020

J Immunother Cancer

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“…Similar to TIGIT, CD96 has also recently attracted interest as a potential target for anti-tumor therapy. 143 Namely, publications addressing the function of murine CD96 using knockout mice suggested a predominantly inhibitory function in NK cells. Consequently, mice lacking CD96 are more resistant to MCAinduced fibrosarcomas, and the authors proposed that this resistance is not due to direct NK cytotoxicity but increased production of cytokines, particularly IFNγ.…”

Section: Recombinant Oncolytic Poliovirusesmentioning

confidence: 99%

Targeting PVR (CD155) and its receptors in anti-tumor therapy

Brlić

Roviš

Cinamon³

et al. 2018

Cell Mol Immunol

126

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Poliovirus receptor (PVR, CD155) has recently been gaining scientific interest as a therapeutic target in the field of tumor immunology due to its prominent endogenous and immune functions. In contrast to healthy tissues, PVR is expressed at high levels in several human malignancies and seems to have protumorigenic and therapeutically attractive properties that are currently being investigated in the field of recombinant oncolytic virotherapy. More intriguingly, PVR participates in a considerable number of immunoregulatory functions through its interactions with activating and inhibitory immune cell receptors. These functions are often modified in the tumor microenvironment, contributing to tumor immunosuppression. Indeed, increasing evidence supports the rationale for developing strategies targeting these interactions, either in terms of checkpoint therapy (i.e., targeting inhibitory receptors) or in adoptive cell therapy, which targets PVR as a tumor marker.

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“…Necl-5 is often highly upregulated on tumor cells and increased expression of necl-5 correlates with poor prognosis and enhanced resistance to chemotherapy, most likely through inhibition of killing by NK cells expressing CD96. Consistent with this idea, blocking the CD96-necl-5 interaction in vivo with anti-CD96 monoclonal antibodies inhibited experimental metastases in several mouse tumor models (Georgiev et al, 2018). In this regard, antibodies that enhance T cell anti-tumor immune responses by blocking the interaction of the T cell inhibitory receptors CTLA-4 and PD-1 with inhibitory ligands on tumor cells (so-called immune checkpoint inhibitors) have proven very successful therapeutics.…”

mentioning

confidence: 84%

“…However, loss of E-cadherin expression sensitizes tumor cells to NK-mediated cytotoxicity through KLRG1 (Chockley et al, 2018). By contrast, as noted above, tumor cells upregulate necl-5 as a defense mechanism to escape elimination by NK cells expressing CD96 (Georgiev et al, 2018). The CD96-necl-5 structure should accelerate the development of antibodies and potentially small molecules, targeting this interaction as a means to release the brakes on NK-mediated tumor cell killing.…”

Section: Previewsmentioning

confidence: 97%

“…In this issue of Structure, Deuss et al (2019) report the crystal structure of the NK inhibitory receptor CD96 in complex with nectin-like protein-5 (necl-5; CD155) ( Figure 1A). In addition to deepening our appreciation of the multiplicity of solutions NK receptors have evolved to recognize non-MHC ligands (Li and Mariuzza, 2014), the CD96-necl-5 structure is of special interest because CD96 has emerged as potential target for human cancer immunotherapy (Georgiev et al, 2018). Necl-5 binds to nectin-3 to assist in the establishment of adherens junctions between tissue cells (Rikitake et al, 2012).…”

mentioning

confidence: 99%

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