Abstract
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been reported to mediate both tumorigenic and anti-tumor effects in vivo. Blockade of the CEACAM1 signaling pathway has recently been implicated as a novel mechanism for cancer immunotherapy. CC1, a mouse anti-CEACAM1 monoclonal antibody (mAb), has been widely used as a pharmacological tool in preclinical studies to inform on CEACAM1 pathway biology although limited data are available on its CEACAM1 blocking characteristics or pharmacodynamic-pharmacokinetic profiles. We sought to investigate CEACAM1 expression on mouse tumor and immune cells, characterize CC1 mAb binding, and evaluate CC1 in syngeneic mouse oncology models as a monotherapy and in combination with an anti-PD-1 mAb. CEACAM1 expression was observed at high levels on neutrophils, NK cells and myeloid-derived suppressor cells (MDSCs), while the expression on tumor-infiltrating CD8+ T cells was low. Unexpectedly, rather than blocking, CC1 facilitated binding of soluble CEACAM1 to CEACAM1 expressing cells. No anti-tumor effects were observed in CT26, MBT2 or A20 models when tested up to 30 mg/kg dose, a dose that was estimated to achieve >90% target engagement in vivo. Taken together, tumor infiltrating CD8+ T cells express low levels of CEACAM1 and CC1 Ab mediates no or minimal anti-tumor effects in vivo, as a monotherapy or in combination with anti-PD-1 treatment.
Highlights
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), known as CD66a or biliary glycoprotein-1, is a multifunctional transmembrane protein expressed in diverse cell types, including epithelial cells and certain cells of the immune system
We found that CEACAM1 was expressed at relatively high levels on freshly harvested tumor infiltrating B, NK cells, and myeloid-derived suppressor cells (MDSCs), the proportion of these cells was low
Our findings diverge from previously published observations in which CEACAM1 was identified as a marker of exhausted T cells in the tumor microenvironment with majority of the CD8+ T cells in human melanoma samples expressing CEACAM1 by IHC [20]
Summary
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), known as CD66a or biliary glycoprotein-1, is a multifunctional transmembrane protein expressed in diverse cell types, including epithelial cells and certain cells of the immune system. CEACAM1, like other structurally related CEACAM 3-8 proteins, is a member of the Ig superfamily with a basic structure of sequentially ordered Ig-like domains. This protein serves as an adhesion molecule via homophilic and heterophilic interactions and participates in multiple physiological and pathophysiological cell to cell processes [1,2,3,4]. Other investigations have suggested a role for CEACAM1 in angiogenesis and suppression of the neoantigen-specific anti-tumor response [3]
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