Tumor-associated, Estrogen Receptor-related Antigen EBAG9: Linking Intracellular Vesicle Trafficking, Immune Homeostasis, and Malignancy

Recently, in an intriguing study, Ruder et al. reported that an estrogen receptor-related, ubiquitous intra- and extracellular protein produced at increased amounts by human cancer cells, acted as a novel inhibitor of the adaptive immune response, potentially influencing the growth and spread of malignancies (1, 2). Cytotoxic T-lymphocytes (CTLs) and natural killer cells (NKs) of, respectively, the adaptive and innate branches of the mammalian immune system, are crucial for immune surveillance and homeostasis. These cell types recognize and kill “non-self” cell populations, including tumor cells, cells infected by viruses or other pathogens, and those damaged by irradiation, toxic substances, etc. (3–5). CTLs recognize non-self cells via interaction of their specific T-cell receptors (TCRs) with foreign antigens co-expressed with the major histocompatibility (MHC) class I molecules on the surface of target cells. NKs, on the other hand, recognize non-self cells based on the absence of MHC class I expression on these cells, through receptors expressed on the surface of the NK cells. Such receptors include the CD94/NKG2 heterodimer receptor, Ly49, KIR (kill-cell immunoglobulin-like receptor), and ILT (leukocyte inhibitory receptor). Once CTLs and NKs recognize their target cells, they form with them a cell contact region reminiscent of a neural synapse, referred to as “immunological synapse,” and empty into this intercellular gap their secretory lysosomes (or lytic granules) (6, 7) (Figure 1A). The liberated granule hydrolases (i.e., granzymes) then enter the cytoplasm of the target cells with the assistance of another lysosomal protein, perforin, where they activate both caspase-dependent and -independent cell death pathways, finally causing their demise (4) (Figure 1B).