Homophilic adhesion of human CEACAM1 involves N-terminal domain interactions: structural analysis of the binding site

Watt, Suzanne M.; Teixeira, Ana Maria; Zhou, Guang Qian; Doyonnas, Régis; Zhang, Youyi; Fritz, Günter; Blumberg, Richard S.; Kuroki, Masahide; Skubitz, Keith M.; Bates, Paul A.

doi:10.1182/blood.v98.5.1469

Cited by 97 publications

(126 citation statements)

References 65 publications

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“…MRG1 is a potent blocker of intercellular homophilic CEACAM1 interactions MRG1, a mAb selected from a library of antibodies against CEACAM1, is specific to the N-domain of CEA-CAM1, which plays a critical role in CEACAM1 binding (12,13), and exerts an affinity of 1.46 to 2.83 nmol/L, as determined with surface plasmon resonance (Supplementary Fig. 1S).…”

Section: Resultsmentioning

confidence: 99%

“…It is subjected to alternative splicing that raises 2 forms of cytosolic tail, a long form containing immunodominant tyrosine-based inhibitory motif (ITIM) and a short form devoid of ITIM (11). CEACAM1 interacts homophilically with CEA-CAM1 (12) and heterophilically with CEACAM5 but not with other CEACAM proteins (13). CEACAM1 is expressed on a variety of cells, for example, some epithelial cells, melanoma, and activated lymphocytes (10).…”

Section: Introductionmentioning

confidence: 99%

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Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Ortenberg

Sapir

Raz

et al. 2012

Molecular Cancer Therapeutics

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CEACAM1 (biliary glycoprotein-1, CD66a) was reported as a strong clinical predictor of poor prognosis in melanoma. We have previously identified CEACAM1 as a tumor escape mechanism from cytotoxic lymphocytes. Here, we present substantial evidence in vitro and in vivo that blocking of CEACAM1 function with a novel monoclonal antibody (MRG1) is a promising strategy for cancer immunotherapy. MRG1, a murine IgG1 monoclonal antibody, was raised against human CEACAM1. It recognizes the CEACAM1-specific N-domain with high affinity (K D $ 2 nmol/L). Furthermore, MRG1 is a potent inhibitor of CEACAM1 homophilic binding and does not induce any agonistic effect. We show using cytotoxicity assays that MRG1 renders multiple melanoma cell lines more vulnerable to T cells in a dose-dependent manner, only following antigen-restricted recognition. Accordingly, MRG1 significantly enhances the antitumor effect of adoptively transferred, melanoma-reactive human lymphocytes using human melanoma xenograft models in severe combined immunodeficient/nonobese diabetic (SCID/NOD) mice. A significant antibody-dependent cell cytotoxicity response was excluded. It is shown that MRG1 reaches the tumor and is cleared within a week. Importantly, approximately 90% of melanoma specimens are CEACAM1 þ , implying that the majority of patients with melanoma could be amenable to MRG1-based therapy. Normal human tissue microarray displays limited binding to luminal epithelial cells on some secretory ducts, which was weaker than the broad normal cell binding of other anticancer antibodies in clinical use. Importantly, MRG1 does not directly affect CEACAM1 þ cells. CEACAM1 blockade is different from other immunomodulatory approaches, as MRG1 targets inhibitory interactions between tumor cells and late effector lymphocytes, which is thus a more specific and compartmentalized immune stimulation with potentially superior safety profile.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Ortenberg

Sapir

Raz

et al. 2012

Molecular Cancer Therapeutics

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“…The function of the extracellular cleavage of CEACAM1-4L is currently unknown. Because homophilic binding of CEACAM1 isoforms critically depends on the presence of the N-terminal domain (Watt et al, 2001), removal of the N-domain may result in a dissociation of CEACAM1 molecules. This may provide a mechanism, which abrogates continuous signalling through the CEACAM1 pathway.…”

Section: Activation and Processing Of Ceacam1 During Apoptosis S Nittmentioning

confidence: 99%

The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1

et al. 2008

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Marked reduction in apoptosis is a hallmark of early colon tumour growth and the vast majority of these tumours exhibit a loss of expression of the glycoprotein carcinoembryonic-antigen-related cell adhesion molecule 1 (CEACAM1). We recently reported that the CEACAM1 functions as a mediator of apoptosis implicating this cell surface protein in early tumour development. However, the mechanistic involvement of CEACAM1 in cell death pathways is unclear. Here, we show that apoptosis triggers cleavage of the long form of CEACAM1 (CEACAM1-4L) at intracellular and extracellular sites in Jurkat cells and HEK293 cells. Signalling through CEACAM1 leads to caspase activation including caspase-1 and -3 and also involves non-caspase proteases. Moreover, we provide evidence that the naturally occurring CEACAM family member CEA is an inducer of CEACAM1-mediated apoptosis in HT29 colon cancer cells, an effect that depends on the abundance of CEACAM1 on the cell surface. Together, our results demonstrate that the CEACAM1-dependent cell death pathway involves dual cleavage of CEACAM1 and caspase activation and can be activated by CEA.

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“…Anti-CEACAM1 antibodies and soluble recombinant CEA-CAM1-Fc fusion proteins are able to mimic these interactions [11,14]. Binding of these ligands to CEACAM1 induces signaling cascades which regulate cell proliferation [11], tumor growth [15], angiogenesis [16], differentiation of dendritic cells [17], T cell cytotoxicity [18], T cell-and B cell-mediated immune responses [12,19] and apoptosis [20].…”

Section: Introductionmentioning

confidence: 99%

CEACAM1 (CD66a) mediates delay of spontaneous and Fas ligand-induced apoptosis in granulocytes

et al. 2005

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Granulocytes form the first and fastest line of defense against pathogenic infections. Their survival is limited by apoptosis, a process that is critical for the resolution of inflammation. Pro-apoptotic and pro-inflammatory cytokines, as well as several receptors, can alter the lifespan of granulocytes. Here we report that the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CD66a) is involved in the regulation of granulocyte survival. Until now CEACAM1 is described to control cell proliferation, cell migration, tumor growth, angiogenesis and diverse leukocyte functions. However, very little is known about its role in granulocytes. We found that CEACAM1 expression in resting rat granulocytes is significantly higher than in other leukocyte subtypes. Stimulation led to a strongly increased CEACAM1 cell surface expression and to release of soluble CEACAM1. DNA fragmentation assays and annexin V staining revealed that binding of CEACAM1-specific antibodies, Fab fragments and soluble CEACAM1-Fc constructs to cell surface-expressed CEACAM1 causes a delay of spontaneous and Fas ligand (CD95L)-induced apoptosis. Tyrosine phosphorylation of CEACAM1-L, its association with SHP-1, the activation of Erk1/2 and caspase-3 appeared to be crucial for the CEACAM1-mediated anti-apoptotic effect. These findings provide evidence that CEACAM1 influences the resolution of inflammation by prolonging the survival of rat granulocytes.

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Homophilic adhesion of human CEACAM1 involves N-terminal domain interactions: structural analysis of the binding site

Cited by 97 publications

References 65 publications

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1

CEACAM1 (CD66a) mediates delay of spontaneous and Fas ligand-induced apoptosis in granulocytes

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