To express or not to express HLA-G: tissue undifferentiation is the answer in gastrointestinal tumors

Human leukocyte antigen G (HLA G) is a non-classical HLA class I molecule with, potent tolerogenic activity, mainly restricted to immune-privileged tissues under, physiological conditions. However, aberrant HLA G expression has been increasingly, reported in tumors, where it acts as an immune checkpoint contributing to evasion from, cytotoxic T and NK cell responses. In this review, we integrate current knowledge on, the molecular regulation and immunological roles of HLA G with original findings from, gastric and colorectal adenocarcinoma cohorts of similar demographic and geographic, origin. Genetic analyses revealed that polymorphisms associated with increased HLA,G expression such as the 14 bp deletion and + 3142C variants in the 3'UTR, region-were significantly enriched in gastric cancer but not in colorectal cancer, suggesting tissue-specific genetic modulation of HLA G expression. Immunohistochemical examination of tumor samples showed that HLA G protein, expression was present in both gastric (41.2%) and colorectal (36.4%), adenocarcinomas, while absent from matched non-tumoral mucosa. Strikingly, HLA G, positivity correlated with histologically undifferentiated tumor subtypes (diffuse or grade, 3), indicating that dedifferentiation is a key determinant of its expression. These HLA, G-high tumors likely generate an immunosuppressive microenvironment through the, HLA G/ILT2 axis, functionally impairing ILT2+ cytotoxic T lymphocytes analogously to, classical PD 1/PD L1 pathways. Altogether, our data suggest that tumor dedifferentiation and loss of epithelial identity promote HLA G induction, endowing, tumors with stem like, immune resistant properties. Consequently, HLA G expression, and its receptor interactions emerge as potential biomarkers of poor prognosis and, feasible targets for therapeutic blockade in gastrointestinal cancers, particularly those, refractory to conventional immune checkpoint inhibitors.