CEACAM1-3S Drives Melanoma Cells into NK Cell-Mediated Cytolysis and Enhances Patient Survival

Abstract

CEACAM1 is a widely expressed multifunctional cell-cell adhesion protein reported to serve as a poor prognosis marker in melanoma patients. In this study, we examine the functional and clinical contributions of the four splice isoforms of CEA-CAM1. Specifically, we present in vitro and in vivo evidence that they affect melanoma progression and immune surveillance in a negative or positive manner that is isoform specific in action. In contrast with isoforms CEACAM1-4S and CEACAM1-4L, expression of isoforms CEACAM1-3S and CEACAM1-3L is induced during disease progression shown to correlate with clinical stage. Unexpectedly, overall survival was prolonged in patients with advanced melanomas expressing CEACAM1-3S. The favorable effects of CEACAM1-3S related to enhanced immunogenicity, which was mediated by cell surface upregulation of NKG2D receptor ligands, thereby sensitizing melanoma cells to lysis by natural killer cells. Conversely, CEA-CAM1-4L downregulated cell surface levels of the NKG2D ligands MICA and ULBP2 by enhanced shedding, thereby promoting malignant character. Overall, our results define the splice isoform-specific immunomodulatory and cell biologic functions of CEACAM1 in melanoma pathogenesis. Cancer Res; 75(9); 1897-907. Ó2015 AACR.

MITF is a critical regulator of the carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) in malignant melanoma

“…The progression of melanoma is a complex multistep process orchestrated by a variety of cellular factors (Bastian, ). Although loss or reduced levels of the multifunctional carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) expression have been detected in several tumor types, including colon (Neumaier et al., ), prostate (Luo et al., ), and breast cancer (Riethdorf et al., ), neo‐expression of CEACAM1 acts as a driver of melanoma cell invasion, thereby favoring metastatic spread (Ebrahimnejad et al., ; Markel et al., ; Ortenberg et al., ; Thies et al., ; Ullrich et al., ).…”

“…Around 80% of all malignant melanoma lesions express CEACAM1 (Ortenberg et al., ; Ullrich et al., ), and moreover, its expression impacts on melanoma cell immunogenicity (Chen et al., ; Ullrich et al., ). Understanding the role of CEACAM1 and what drives its tightly controlled expression in melanoma is a key issue that may offer insights into the process of melanoma progression.…”

Roles of CEACAM1 in cell communication and signaling of lung cancer and other diseases

“…The expression of CEAC AM1 varies between tumors. It is down-regulated in colon carcinomas, hepatocellular carcinomas, renal cancer, and breast cancer, while up-regulated in metastatic and malignant melanomas and lung cancer [2,3]. CEACAM1 acts as a pathogen receptor and plays the important role in cell proliferation, angiogenesis, apoptosis, and tumor metastasis [4].…”

MITF and cell migration: opposing signals, similar outcome

“…showing that MITF stimulates the expression of the gene encoding the cell adhesion molecule CEACAM1 (Ullrich et al., ). Based on previous studies, overexpression of CEACAM1 in melanoma cells increases cell invasion and migration (Ebrahimnejad et al., ; Ullrich et al., ) likely through mechanisms involving interaction with β‐integrin and filamin (Brummer et al., ; Klaile et al., ) as well as N‐cadherin (Liu et al., ). On the other hand, we recently observed that another cellular adhesion molecule, MCAM, also known as CD146, is repressed by MITF in mouse melanoblasts (melb‐a cells), a repression that leads to inhibition of melanoblast migration (Rao et al., ).…”

“…As usual, however, details are important. The evidence that CEACAM1 promotes migration is based on overexpression (Ullrich et al., ), that is, under conditions where MITF levels are low and hence different from the more physiological conditions where MITF and CEACAM1 levels go hand in hand. In fact, to our knowledge, the role of CEACAM1 in invasion has not yet been confirmed by experimental downregulation in an invasive melanoma.…”