Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)–Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) axis (CEACAM5–CEACAM1 axis)

The Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)–Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) axis is a significant immune checkpoint pathway in oncology. CEACAM5, also known as CEA, is a cell surface glycoprotein primarily expressed in embryonic tissues and overexpressed in various carcinomas, including colorectal, lung, and pancreatic cancers (UniProt P06731). CEACAM1 is expressed on both tumor cells and immune cells, such as T cells and natural killer (NK) cells, where it functions as an inhibitory receptor (UniProt P13688). The heterophilic interaction between CEACAM5 on tumor cells and CEACAM1 on immune cells leads to the recruitment of SHP-1/2 phosphatases to the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of CEACAM1, thereby suppressing T-cell activation and effector functions (PubMed: 24516127). This interaction facilitates tumor immune evasion by creating an immunosuppressive microenvironment. Therapeutic targeting of this axis involves monoclonal antibodies designed to block the CEACAM5–CEACAM1 interaction or antibody-drug conjugates (ADCs) like Tusamitamab ravtansine that target CEACAM5-expressing cells for destruction (ClinicalTrials.gov: NCT04154956). Disrupting this axis aims to restore the anti-tumor activity of the host immune system while providing a mechanism for targeted cytotoxicity in CEA-positive malignancies. Clinical development has focused on patient populations with high CEACAM5 expression, utilizing it as both a target and a predictive biomarker for efficacy.

Other names

CEA-CEACAM1 axisCD66e-CD66a axisCEACAM5-CEACAM1 interactionCEACAM5-CEACAM1 immune checkpoint

The mechanism involves blocking the heterophilic binding between CEACAM5 and CEACAM1 to prevent the recruitment of inhibitory phosphatases (SHP-1/2) to immune cells, thereby enhancing T-cell and NK-cell mediated tumor lysis (PubMed: 24516127). Additionally, CEACAM5-targeted antibody-drug conjugates (ADCs) deliver cytotoxic payloads directly to tumor cells overexpressing the antigen (ClinicalTrials.gov: NCT04154956).