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CD56 is an adhesion molecule mediating homophilic and heterophilic adhesion in neurons, natural killer cells, and a small subset of CD4- and CD8-positive T cells. It is expressed in tumors with neuroendocrine differentiation (small cell lung carcinoma and neural-derived tumors) or natural killer cell lineage (subset of lymphomas). In normal small intestine, the ganglion cells in the muscle wall and nerves will show strong staining. Scattered lymphocytes may also be positive.

CD56 is the archetypal phenotypic marker of natural killer cells but can actually be expressed by many more immune cells, including alpha beta T cells, gamma delta T cells, dendritic cells, and monocytes.

The neural cell adhesion molecule (NCAM), also known as CD56, is a member of the immunoglobulin superfamily engaged in both so-called homophilic and heterophilic interactions. Three main isoforms exist of CD56 (NCAM-120, NCAM-140, and NCAM-180), all generated by alternative splicing from one single gene, differing in their intracellular domain length.

CD56 is often considered a marker of neural lineage commitment due to its discovery site. However, CD56 expression is also found in, among others, the hematopoietic system. Here, the expression of CD56 is most stringently associated with, but certainly not limited to, natural killer (NK) cells.

CD56 has been detected on other lymphoid cells, including gamma delta T cells and activated CD8+ T cells, as well as on dendritic cells (DCs).

Also, in the bone marrow, at the site where hematopoiesis occurs, CD56 fulfills a pivotal role. Mesenchymal stromal cells provide niches for hematopoietic stem cells by, inter alia, the expression of adhesion molecules comprising CD56, maintaining long-term hematopoiesis.

On the other hand, aberrant CD56 expression is seen in a range of hematological malignancies [e.g., multiple myeloma and leukemia] as well as solid tumors [e.g., lung cancer, ovarian cancer, and neuroblastoma]. Moreover, numerical and functional deficiencies and phenotypic alterations of CD56+ immune cells have been reported in patients with various infectious, autoimmune or malignant diseases.


Van Acker HH, Capsomidis A, Smits EL, Van Tendeloo VF. CD56 in the Immune System: More Than a Marker for Cytotoxicity? Front Immunol. 2017 Jul 24;8:892. doi: 10.3389/fimmu.2017.00892. PMID: 28791027; PMCID: PMC5522883.

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