Structural principles of tumor necrosis factor superfamily signaling

Vanamee, Eva; Faustman, Denise L.

doi:10.1126/scisignal.aao4910

Cited by 215 publications

(258 citation statements)

References 96 publications

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“…Additionally, the CD137L expression on HCC‐827 cells significantly induced IFN‐γ production because this could be completely inhibited by treatment with anti‐CD137 mAb. It has been suggested that CD137 is sensitive to stimulation by CD137L, so even these low expression levels might be sufficient to trigger CD137 signaling upon interaction with CD137L. More interestingly, we found that anti‐CD137 mAb can also induce the expression of PD‐L1 in lung cancer cells and synergize with IFN‐γ.…”

Section: Discussionmentioning

confidence: 53%

CD137 ligand feedback upregulates PD‐L1 expression on lung cancer via T cell production of IFN‐γ

et al. 2019

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Background The expression of PD‐L1 and its regulation in tumors remains unclear. The importance of IFN‐γ in upregulating the PD‐L1 expression in various tumors, and the effects of other essential cytokines in the tumor microenvironment (TME), need to be further elucidated. Methods Constitutive expression of PD‐L1 and CD137L in all 13 lung cancer cell lines were tested by flow cytometry. CD137L mRNA of lung cancer cell lines was detected by RT‐PCR. PD‐L1 expression rates following stimulation with these cytokines (IFN‐γ, TNFα and IL2) were measured. After coculture of cells expressing CD137L (lung cancer cells or 293FT cells transfected with CD137L plasmid) with T cells, the PDL1 expression of lung cancer cells and IFN‐γ in supernatant was detected. Results Our data revealed that adenocarcinoma and squamous cell carcinoma cells had the highest positive expression rate. IFN‐γ was the core‐inducing factor for enhancing the PD‐L1 expression. CD137L was also widely expressed in the lung cancer cell lines at the mRNA level, whereas its expression was generally low at the protein level. However, the low expression of CD137L protein was still enough to induce T cells to produce IFN‐γ, which subsequently increased the PD‐L1 expression by lung cancer cells. The CD137 signal induces IFN‐γ secretion by T cells, which stimulates high‐level of PD‐L1 expression in cancer cells; this negative immune regulation may represent a mechanism of immune escape regulation. Conclusions CD137L mRNA was widely expressed in lung cancer cell lines whereas levels of protein expression were generally low. The low level of CD137L protein was still enough to induce T cells to produce IFN‐γ that subsequently increased PD‐L1 expression. The CD137L‐induced negative immune regulation may represent a mechanism of immune escape.

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Section: Discussionmentioning

confidence: 53%

CD137 ligand feedback upregulates PD‐L1 expression on lung cancer via T cell production of IFN‐γ

et al. 2019

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“…Caspase 8) causing apoptosis [18, 29, 30]. Conversely, when TNF-alpha activates TNF-R2, recruitment of the TNF receptor-associated factors (TRAF2) occurs, resulting in stimulation of NF-kappa B, which possesses anti-apoptotic properties [19, 31]. TNF-R1 is the high affinity receptor which is internalized upon ligation whereas TNF-R2 is shed [32].…”

Section: Tnf-alpha Receptors 1 Andmentioning

confidence: 99%

Unleashing endogenous TNF-alpha as a cancer immunotherapeutic

Josephs¹,

Ichim

Prince³

et al. 2018

J Transl Med

194

151

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Tumor necrosis factor (TNF)-alpha was originally identified in the 1970s as the serum mediator of innate immunity capable of inducing hemorrhagic necrosis in tumors. Today, a wide spectrum of biological activities have been attributed to this molecule, and clinical translation has mainly occurred not in using it to treat cancer, but rather to inhibit its effects to treat autoimmunity. Clinical trials utilizing systemic TNF-alpha administration have resulted in an unacceptable level of toxicities, which blocked its development. In contrast, localized administration of TNF-alpha in the form of isolated limb perfusion have yielded excellent results in soft tissue sarcomas. Here we describe a novel approach to leveraging the potent antineoplastic activities of TNF-alpha by enhancing activity of locally produced TNF-alpha through extracorporeal removal of soluble TNF-alpha receptors. Specifically, it is known that cancerous tissues are infiltrated with monocytes, T cells, and other cells capable of producing TNF-alpha. It is also known that tumors, as well as cells in the tumor microenvironment produce soluble TNF-alpha receptors. The authors believe that by selectively removing soluble TNF-alpha receptors local enhancement of endogenous TNF-alpha activity may provide for enhanced tumor cell death without associated systemic toxicities.

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“…FAS is the sixth member of the tumor necrosis factor receptor superfamily (TNFRSF6). It is the prototypic member of the death receptor subfamily, which includes the TNFRSF‐1a, ‐6, ‐10a, ‐10b, ‐12, and ‐23 proteins . All the death receptors have an intracellular death domain (DD) comprising 60‐80 amino acid residues (DD).…”

Section: Lymphocyte Apoptosis: Extrinsic Versus Intrinsic Pathwaysmentioning

confidence: 99%

“…It is the prototypic member of the death receptor subfamily, which includes the TNFRSF-1a, -6, -10a, -10b, -12, and -23 proteins. 6 All the death receptors have an intracellular death domain (DD) comprising 60-80 amino acid residues (DD). Upon interaction with FAS-ligand (FASLG), a conformational modification leads to the recruitment of a cytoplasmic adapter (the FAS-associated protein with death domain, FADD) via homotypic interactions with the DD.…”

Section: Lympho C Y Te Ap Op Tos Is: E X Trin S I C Ver Sus Intrinmentioning

confidence: 99%

FAS and RAS related Apoptosis defects: From autoimmunity to leukemia

Meynier

Rieux-Laucat

2018

Immunological Reviews

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Summary The human adaptive immune system recognizes almost all the pathogens that we encounter and all the tumor antigens that may arise during our lifetime. Primary immunodeficiencies affecting lymphocyte development or function therefore lead to severe infections and tumor susceptibility. Furthermore, the fact that autoimmunity is a frequent feature of primary immunodeficiencies reveals a third function of the adaptive immune system: its self‐regulation. Indeed, the generation of a broad repertoire of antigen receptors (via a unique strategy of random somatic rearrangements of gene segments in T cell and B cell receptor loci) inevitably creates receptors with specificity for self‐antigens and thus leads to the presence of autoreactive lymphocytes. There are many different mechanisms for controlling the emergence or action of autoreactive lymphocytes, including clonal deletion in the primary lymphoid organs, receptor editing, anergy, suppression of effector lymphocytes by regulatory lymphocytes, and programmed cell death. Here, we review the genetic defects affecting lymphocyte apoptosis and that are associated with lymphoproliferation and autoimmunity, together with the role of somatic mutations and their potential involvement in more common autoimmune diseases.

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Structural principles of tumor necrosis factor superfamily signaling

Cited by 215 publications

References 96 publications

CD137 ligand feedback upregulates PD‐L1 expression on lung cancer via T cell production of IFN‐γ

CD137 ligand feedback upregulates PD‐L1 expression on lung cancer via T cell production of IFN‐γ

Unleashing endogenous TNF-alpha as a cancer immunotherapeutic

FAS and RAS related Apoptosis defects: From autoimmunity to leukemia

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