Explore CEA CD3

Redirecting the activity of T cells to engage/restore immunity against tumor cells is a promising area of research in oncology. One approach is based on the recognition of tumor surface antigens, such as carcinoembryonic antigen (CEA), and the simultaneous binding of the CD3ε chain on T cells. This coordinated event may trigger the activation of cytotoxic and helper T cells leading to intratumoral T-cell accumulation, T-cell proliferation, cytokine production, and T-cell–mediated immunity.1

CEA: a tumor surface antigen

Expression of CEA on tumor surface

CEA is a tumor cell surface protein and a member of the immunoglobulin superfamily. Under normal conditions, CEA is mainly expressed at low levels by epithelial cells and is thought to function as an adhesion molecule.2

Numerous studies have evaluated the expression level of CEA in various tumor types through gene expression analysis (RNA) or immunohistochemistry (protein).3,4 Overexpression of CEA in tumor cells compared to normal tissues is seen in colorectal, pancreatic, gastric, lung, breast, head and neck, uterine, and bladder cancers.1,3

CD3: a T-cell activator

CD3 protein T-cell receptor

CD3 is a multimeric protein, composed of 4 subunits (γ, δ, ε, ζ) that form a complex with the T-cell receptor (TCR) on the surface of T cells.5 A conformational change in CD3ε can be triggered by an agonistic protein-protein interaction alone. Activation of the TCR causes a conformational change in the cytoplasmic domain of CD3ε, allowing the recruitment of the adaptor protein Nck. This is essential for T-cell activation/proliferation and subsequent release of cytokines, chemokines, and cytotoxic granules. This process does not require specific antigen recognition via major histocompatibility complex-peptide complex in order to trigger the ability of T cells to deliver the cytotoxic granules that may cause tumor cell lysis.1,5,6

Potential of simultaneous binding of CEA and CD3

 

Image: CEA, and simultaneous binding of CEA and CD3

CEA CD3 interaction is an area of continued research in cancer immunity targets.

Image: CD3, and simultaneous binding of CEA and CD3

Simultaneous binding of CEA on the tumor cell and CD3ε on a T lymphocyte can activate CD3 downstream signaling and the formation of immunologic synapses.1 This may lead to the influx and expansion of T cells into an immunologically inert tumor, resulting in subsequent antitumor immunity.1,3,7

References

  1. Bacac M, Fauti T, Sam J, et al. A novel carcinoembryonic antigen T-cell bispecific antibody (CEA TCB) for the treatment of solid tumors. Clin Cancer Res. 2016;22:3286-3297. PMID: 26861458
  2. Camacho-Leal P, Stanners CP. The human carcinoembryonic antigen (CEA) GPI anchor mediates anoikis inhibition by inactivation of the intrinsic death pathway. Oncogene. 2008;27:1545-1553. PMID: 17891182
  3. Bacac M, Klein C, Umana P. CEA TCB: a novel head-to-tail 2:1 T cell bispecific antibody for treatment of CEA-positive solid tumors. Oncoimmunology. 2016;5:e1203498. PMID: 27622073
  4. Nollau P, Scheller H, Kona-Horstmann M, et al. Expression of CD66a (human C-CAM) and other members of the carcinoembryonic antigen gene family of adhesion molecules in human colorectal adenomas. Cancer Res. 1997;57:2354-2357. PMID: 9192807
  5. Davis MM. A new trigger for T cells. Cell. 2002;110:285-287. PMID: 12176315
  6. Borroto A, Arellano I, Blanco R, et al. Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo. J Immunol. 2014;192:2042-2053. PMID: 24470497
  7. Lehmann S, Perera R, Grimm HP, et al. In vivo fluorescence imaging of the activity of CEA TCB, a novel T-cell bispecific antibody, reveals highly specific tumor targeting and fast induction of T-cell–mediated tumor killing. Clin Cancer Res. 2016;22:4417-4427. PMID: 27117182

Related links

Information based on tumor type