Molecular and biological characterization of a ligand for CD27 defines a new family of cytokines with homology to tumor necrosis factor

doi:10.1016/0092-8674(93)90133-B

Cell

Volume 73, Issue 3, 7 May 1993, Pages 447-456

https://doi.org/10.1016/0092-8674(93)90133-B Get rights and content

Abstract

CD27 is a surface antigen found on T and B cells that has homology to a family of molecules including the receptors for tumor necrosis factor (TNF) and nerve growth factor. A cDNA encoding a ligand for CD27 was isolated by a direct-expression cloning strategy using a fusion protein composed of the extracellular domain of CD27 linked to the constant domain of a human immunoglobulin G1 molecule as a probe. The predicted protein product is a type II transmembrane protein whose gene maps to 19p13 and that shows homology to TNF and the ligand for CD40. Biological characterization indicates that the cloned ligand induces the proliferation of costimulated T cells and enhances the generation of cytolytic T cells.

References (40)

A. Carrier et al.
Cloning and mapping of 5′ exons from the gene encoding chicken beta nerve growth factor
Gene
(1992)
H. Dürkop et al.
Molecular cloning and expression of a new member of the nerve growth factor receptor family that is characteristic for Hodgkin's disease
Cell
(1992)
U. Gubler et al.
A simple and very efficient method for generating cDNA libraries
Gene
(1983)
N. Itoh et al.
The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis
Cell
(1991)
D. Johnson et al.
Expression and structure of the human NGF receptor
Cell
(1986)
H. Loetscher et al.
Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor
Cell
(1990)
B. Mosley et al.
The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane bound forms
Cell
(1989)
T.J. Schall et al.
Molecular cloning and expression of a receptor for human tumor necrosis factor
Cell
(1990)
C.A. Smith et al.
T2 open reading frame from the Shope fibroma virus encodes a soluble form of the TNF receptor
Biochem. Biophys. Res. Commun.
(1991)
D.L. Urdal et al.
Affinity purification and chemical analysis of the interleukin-1 receptor
J. Biol. Chem.
(1988)

M.R. Alderson et al.

Interleukin 7 enhances cytolytic T lymphocyte generation and induces lymphokine-activated killer cells from human peripheral blood

J. Exp. Med.

(1990)

R.J. Armitage et al.

Molecular and biological characterization of a murine ligand for CD40

Nature

(1992)

B. Beutler et al.

The biology of cachectin/TNF: a primary mediator of the host response

Annu. Rev. Immunol.

(1989)

R.D. Bigler et al.

S152 (CD27): a modulating disulfide-linked T cell activation antigen

J. Immunol.

(1988)

J.L. Browning et al.

Lymphotoxin and an associated 33-kDa glycoprotein are expressed on the surface of an activated human T cell hybridoma

J. Immunol.

(1991)

D.F. Callen et al.

Reassessment of two apparent deletions of chromosome 16p to an ins(11;16) and a t(1;16) by chromosome painting

Ann. Genet.

(1990)

D. Camerini et al.

The T cell activation antigen CD27 is a member of the $NGF TNF$ receptor gene family

J. Immunol.

(1991)

R. de Jong et al.

Regulation of expression of CD27, a T cell-specific member of a novel family of membrane receptors

J. Immunol.

(1991)

S.K. Dower et al.

The interaction of monoclonal antibodies with MHC class I antigens on mouse spleen cells. I. Analysis of the mechanism of binding

J. Immunol.

(1984)

W.C. Fanslow et al.

Soluble forms of CD40 inhibit biological responses of human B cells

J. Immunol.

(1992)

Cited by (285)

Targeting CD70 in cutaneous T-cell lymphoma using an antibody-drug conjugate in patient-derived xenograft models
2022, Blood Advances
Citation Excerpt :
CD70 has several unique properties that make it an ideal therapeutic target in cancer. First, CD70 is only transiently expressed on activated T- and B-lymphocytes, mature killer cells, and mature dendritic cells,5-9 and has limited expression on normal, nonimmune cells. However, it is more widely expressed in various solid tumors and hematologic malignancies, including various subtypes of B-cell and systemic T-cell lymphomas.
CD70 is a member of the tumor necrosis factor receptor superfamily. Emerging data indicate that CD70 may be a suitable target for various malignancies. We investigated the expression of CD70 in cutaneous and systemic T-cell lymphomas and conducted preclinical studies of SGN-CD70A, a CD70-directed antibody-drug conjugate (ADC), using patient-derived xenograft cutaneous T-cell lymphoma (CTCL PDX) models. CD70 expression was examined by immunohistochemical (IHC) stains in 49 diagnostic specimens of T-cell lymphomas. The activities of SGN-CD70A in growth inhibition and apoptosis induction were examined in CTCL cell lines and primary CTCL tumor cells. Using previously established CTCL PDXs, we conducted a dose-finding trial followed by a phase 2-like trial to evaluate the optimal dosing and the efficacy of SGN-CD70A in tumor-bearing PDX animals. The therapeutic efficacy of SGN-CD70A was measured by tumor-associated cell-free DNA (cfDNA) and survival of treated PDXs. We found that CD70 is highly expressed in T-cell lymphomas, especially in CTCL. SGN-CD70A inhibited cell growth and induced apoptosis in CD70-expressing CTCL cell lines and primary tumors cells. Additionally, SGN-CD70A at 100 μg/kg and 300 μg/kg prolonged the survival of PDXs in a dose-dependent manner. Finally, treatment with 3 doses of SGN-CD70A at 300 μg/kg was superior to a single-dose treatment in survival prolongation (median survival: 111 days vs 39 days; P = .017). Most importantly, multiple dosing of SGN-CD70A induced complete eradication of established tumors in PDXs measured by cfDNA. Our results demonstrated marked antitumor activity of SGN-CD70A in CTCL PDXs, providing compelling support for its clinical investigation.
Structural delineation and phase-dependent activation of the costimulatory CD27:CD70 complex
2021, Journal of Biological Chemistry
CD27 is a tumor necrosis factor (TNF) receptor, which stimulates lymphocytes and promotes their differentiation upon activation by TNF ligand CD70. Activation of the CD27 receptor provides a costimulatory signal to promote T cell, B cell, and NK cell activity to facilitate antitumor and anti-infection immunity. Aberrant increased and focused expression of CD70 on many tumor cells renders CD70 an attractive therapeutic target for direct tumor killing. However, despite their use as drug targets to treat cancers, the molecular basis and atomic details of CD27 and CD70 interaction remain elusive. Here we report the crystal structure of human CD27 in complex with human CD70. Analysis of our structure shows that CD70 adopts a classical TNF ligand homotrimeric assembly to engage CD27 receptors in a 3:3 stoichiometry. By combining structural and rational mutagenesis data with reported disease-correlated mutations, we identified the key amino acid residues of CD27 and CD70 that control this interaction. We also report increased potency for plate-bound CD70 constructs compared with solution-phase ligand in a functional activity to stimulate T-cells in vitro. These findings offer new mechanistic insight into this critical costimulatory interaction.
CD70 antibody-drug conjugate as a potential therapeutic agent for uterine leiomyosarcoma
2021, American Journal of Obstetrics and Gynecology
Uterine leiomyosarcoma is a rare and aggressive gynecologic malignancy originating in the myometrium of the uterine corpus that tends to recur even after complete surgical excision. Current therapeutic agents have only modest effects on uterine leiomyosarcoma. Although antibodies and antibody-drug conjugates have been recognized as useful targeted therapies for other cancers, no study has yet evaluated the effects of this approach on uterine leiomyosarcoma.
This study aimed to examine the activity of tumoral CD70 in uterine leiomyosarcoma and assess the antitumor activity of CD70–antibody-drug conjugate treatment in uterine leiomyosarcoma.
Target membrane proteins were screened by profiling and comparing membrane protein expression in 3 uterine leiomyosarcoma cell lines (SK-UT-1, SK-LMS-1, and SKN) and normal uterine myometrium cells using the isobaric tags for relative and absolute quantitation labeling method. Western blotting, fluorescence-activated cell sorting analyses, and immunohistochemistry were used to examine CD70 expression in the membrane proteins in uterine leiomyosarcoma cell lines and clinical samples. We developed an antibody-drug conjugate with a monoclonal antibody of the target membrane protein linked to monomethyl auristatin F and investigated its antitumor effects against uterine leiomyosarcoma (in vitro, in vivo, and in patient-derived xenograft models).
CD70 was identified as a specific antigen highly expressed in uterine leiomyosarcoma cell lines. Of the 3 uterine leiomyosarcoma cell lines, CD70 expression was confirmed in SK-LMS-1 cells by western blotting and fluorescence-activated cell sorting analysis. CD70 overexpression was observed in 19 of 21 (90.5%) tumor specimens from women with uterine leiomyosarcoma. To generate CD70–antibody-drug conjugate, anti-CD70 monoclonal antibody was conjugated with a novel derivative of monomethyl auristatin F. CD70–antibody-drug conjugate showed significant antitumor effects on SK-LMS-1 cells (half maximal inhibitory concentration, 0.120 nM) and no antitumor effects on CD70-negative uterine leiomyosarcoma cells. CD70–antibody-drug conjugate significantly inhibited tumor growth in the SK-LMS-1 xenograft mouse model (tumor volume, 129.8 vs 285.5 mm³; relative reduction, 54.5%; P<.001) and patient-derived xenograft mouse model (tumor volume, 128.1 vs 837.7 mm³; relative reduction, 84.7%; P<.001).
Uterine leiomyosarcoma tumors highly express CD70 and targeted therapy with CD70–antibody-drug conjugate may have a potential therapeutic implication in the treatment of uterine leiomyosarcoma.
Integrating Proteomics and Transcriptomics for Systematic Combinatorial Chimeric Antigen Receptor Therapy of AML
2017, Cancer Cell
Citation Excerpt :
The majority of our AML cases showed strong CCR1 expression, averaging 88% positivity by FACS in all specimens. CD70 is a member of the tumor necrosis factor family and the ligand of the CD27 T cell co-stimulatory receptor (Bowman et al., 1994; Goodwin et al., 1993). It is expressed in multiple tumor types and serves as a target for antibody and drug-conjugated antibody depletion in both renal cell carcinoma and non-Hodgkin’s lymphoma (Law et al., 2006; McEarchern et al., 2007, 2008; Ryan et al., 2010).
Chimeric antigen receptor (CAR) therapy targeting CD19 has yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for overexpressed molecules with tolerable systemic expression. We integrated large transcriptomics and proteomics datasets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34⁺CD38⁻ hematopoietic cells, T cells, or vital tissues. As these investigations did not uncover candidate targets with a profile as favorable as CD19, we developed a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria. Our findings indicate that several target pairings hold great promise for CAR therapy of AML.
CD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies
2017, Blood
Citation Excerpt :
Interestingly, the expression of CD27 differs in subsets of DLBCL with high expression in the germinal-center–like subtype and low expression in the activated B-cell–like subtype.11 After ligation of CD27 with its unique ligand CD70,12 a soluble form of CD27 (sCD27) is released to the sera, and the level of sCD27 correlates with lymphoma load.8,13 High sCD27 levels are associated with poor outcome in patients with DLBCL.14
The interaction of the tumor necrosis factor receptor (TNFR) CD27 with its ligand CD70 is an emerging target to treat cancer. CD27 signaling provides costimulatory signals to cytotoxic T cells but also increases the frequency of regulatory T cells. Similar to other TNFR ligands, CD70 has been shown to initiate intracellular signaling pathways (CD70 reverse signaling). CD27 is expressed on a majority of B-cell non–Hodgkin lymphoma, but its role in the immune control of lymphoma and leukemia is unknown. We therefore generated a cytoplasmic deletion mutant of CD27 (CD27-trunc) to study the role of CD70 reverse signaling in the immunosurveillance of B-cell malignancies in vivo. Expression of CD27-trunc on malignant cells increased the number of tumor-infiltrating interferon γ–producing natural killer (NK) cells. In contrast, the antitumoral T-cell response remained largely unchanged. CD70 reverse signaling in NK cells was mediated via the AKT signaling pathway and increased NK cell survival and effector function. The improved immune control by activated NK cells prolonged survival of CD27-trunc–expressing lymphoma-bearing mice. Finally, CD70 reverse signaling enhanced survival and effector function of human NK cells in a B-cell acute lymphoblastic leukemia xenotransplants model. Therefore, CD70 reverse signaling in NK cells contributes to the immune control of CD27-expressing B-cell lymphoma and leukemia.
The early activation of memory B cells from Wiskott-Aldrich syndrome patients is suppressed by CD19 downregulation
2016, Blood
Citation Excerpt :
Most of naive follicular B cells differentiate into plasma cells after clonal expansion, and a small fraction persists as dormant memory B cells after having gone through GC reaction.28 CD27, a membrane protein belonging to the tumor necrosis family receptor, is considered to be the marker of human memory B cells and is associated with somatic mutations in immunoglobulin variable genes.29-31 The BCR clustering and pSyk accumulation in the interface between the B cells and lipid bilayer are increased in immunoglobulin G+ (IgG+) B cells compared with IgM+ cells.32
Wiskott-Aldrich syndrome (WAS) pediatric patients exhibit a deficiency in humoral immune memory. However, the mechanism by which Wiskott-Aldrich syndrome protein (WASP) regulates the differentiation and activation of memory B cells remains elusive. Here we examine the early activation events of memory B cells from the peripheral blood mononuclear cells of WAS patients and age-matched healthy controls (HCs) using total internal reflection fluorescence microscopy. In response to stimulation through the B-cell receptor (BCR), memory B cells from HCs showed significantly higher magnitudes of BCR clustering and cell spreading than naive B cells from the same individuals. This was associated with increases in CD19 recruitment to the BCR and the activation of its downstream signaling molecule Btk and decreases in FcγRIIB recruitment and the activation of its downstream molecule Src homology 2-containing inositol 5′ phosphatase (SHIP). However, these enhanced signaling activities mediated by CD19 and Btk are blocked in memory B cells from WAS patients, whereas the activation of FcγRIIB and SHIP was increased. Although the expression levels of CD19, Btk, and FcγRIIB did not change between CD27⁻ and CD27⁺ B cells of HCs, the protein and mRNA levels of CD19 but not Btk and FcγRIIB were significantly reduced in both CD27⁻ and CD27⁺ B cells of WAS patients, compared with those of HCs. Overall, our study suggests that WASP is required for memory B-cell activation, promoting the activation by positive regulating CD19 transcription and CD19 recruitment to the BCR.

View all citing articles on Scopus

View full text

Cell

ArticleMolecular and biological characterization of a ligand for CD27 defines a new family of cytokines with homology to tumor necrosis factor

Abstract

Gene

Cell

Gene

Cell

Cell

Cell

Cell

Cell

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Interleukin 7 enhances cytolytic T lymphocyte generation and induces lymphokine-activated killer cells from human peripheral blood

J. Exp. Med.

Molecular and biological characterization of a murine ligand for CD40

Nature

The biology of cachectin/TNF: a primary mediator of the host response

Annu. Rev. Immunol.

S152 (CD27): a modulating disulfide-linked T cell activation antigen

J. Immunol.

Lymphotoxin and an associated 33-kDa glycoprotein are expressed on the surface of an activated human T cell hybridoma

J. Immunol.

Reassessment of two apparent deletions of chromosome 16p to an ins(11;16) and a t(1;16) by chromosome painting

Ann. Genet.

The T cell activation antigen CD27 is a member of the NGFTNF receptor gene family

J. Immunol.

Regulation of expression of CD27, a T cell-specific member of a novel family of membrane receptors

J. Immunol.

The interaction of monoclonal antibodies with MHC class I antigens on mouse spleen cells. I. Analysis of the mechanism of binding

J. Immunol.

Soluble forms of CD40 inhibit biological responses of human B cells

J. Immunol.

Article
Molecular and biological characterization of a ligand for CD27 defines a new family of cytokines with homology to tumor necrosis factor

The T cell activation antigen CD27 is a member of the $NGF TNF$ receptor gene family