Size Matters: The Functional Role of the CEACAM1 Isoform Signature and Its Impact for NK Cell-Mediated Killing in Melanoma

Abstract

Malignant melanoma is the most aggressive and treatment resistant type of skin cancer. It is characterized by continuously rising incidence and high mortality rate due to its high metastatic potential. Various types of cell adhesion molecules have been implicated in tumor progression in melanoma. One of these, the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), is a multi-functional receptor protein potentially expressed in epithelia, endothelia, and leukocytes. CEACAM1 often appears in four isoforms differing in the length of their extracellular and intracellular domains. Both the CEACAM1 expression in general, and the ratio of the expressed CEACAM1 splice variants appear very dynamic. They depend on both the cell activation stage and the cell growth phase. Interestingly, normal melanocytes are negative for CEACAM1, while melanomas often show high expression. As a cell⁻cell communication molecule, CEACAM1 mediates the direct interaction between tumor and immune cells. In the tumor cell this interaction leads to functional inhibitions, and indirectly to decreased cancer cell immunogenicity by down-regulation of ligands of the NKG2D receptor. On natural killer (NK) cells it inhibits NKG2D-mediated cytolysis and signaling. This review focuses on novel mechanistic insights into CEACAM1 isoforms for NK cell-mediated immune escape mechanisms in melanoma, and their clinical relevance in patients suffering from malignant melanoma.

Keywords: CEACAM1; NK cells; NKG2D ligands; melanoma.

Figure 1

The four mainly expressed splice variants of human CEACAM1. Alternative splicing of CEACAM1 generates isoforms, which consists of one N-terminal ectodomain followed by either three or four extracellular Ig-like domains, a conserved transmembrane domain, and a short (CEACAM1-4S and 1-3S) or long cytoplasmic (CEACAM1-4L and 1-3L) domain. The long cytoplasmic domain encodes two ITIMs (immunoreceptor tyrosine-based inhibitory motif) that bind SHP-1 and SHP-2 when phosphorylated and convey inhibitory activities to CEACAM1-4L. The short and long cytoplasmic domains have been shown to interact with intracellular molecules such as actin and calmodulin. Interestingly, CEACAM1 is expressed in a cell type and activation stage dependent manner with significant differences in the ratios of its short and long isoforms.

Figure 2

Summary of the natural killer (NK) activation mechanisms modulated by CEACAM1. (top) The interaction of activating receptors on NK cells with activating ligands present on malignant cells facilitates the cytotoxic activity of NK cells and, consequently, the tumor cell lyses. (down) CEACAM1 expression induced in cytokine activated NK cells interacts with tumor cell associated CEACAM1, thus inhibiting the cytolytic function of NK cells.