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

Iris Helfrich,Bernhard Singer

doi:10.3390/cancers11030356

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.

Highlights

Skin Cancer Unit of the Dermatology Department, Medical Faculty, University Duisburg-Essen, West German Cancer Center, Essen 45147, Germany
By interaction with β3 integrin, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-L enhanced the migratory and invasive potential of melanoma cells [61]. In line with this finding, it has been shown that the expression of CEACAM1 in primary cutaneous melanoma predicts the development of metastatic disease [63]
The heterophilic interactions of CEACAM5 with CEACAM1 inhibited the natural killer (NK) cell mediated killing of tumor cells [104]. These findings offered a novel role for the CEACAM5/carcinoembryonic antigen (CEA) protein, enabling the escape of tumor cells from NK-mediated killing, CEA

Summary

Immunosurveillance and NK Cell Signaling in Melanoma

Melanomas often originate from benign nevi consisting of clonally expanded, highly proliferative melanocytes without the tendency for progression. Apart from the cytotoxic T cell-mediated immune response and corresponding promising therapeutic approaches, the down-regulation of the human leukocyte antigen (HLA) class I molecules on melanoma cells represents a considerable problem for T cell-based immunotherapy [15]. In this context, natural killer (NK) cells, which are a lineage of innate lymphocytes, have gained increasing attention as anti-melanoma effector cells due to their preferential targeting of tumor cells with low HLA class I expression [16,17]. MHC class I expression, in order to escape NK-cell mediated tumor cell recognition [30,31]

CEACAM1 Signaling and Its Function in Melanoma

Regulation of NK Cell Function by CEACAM1

Findings

Conclusions