Immune evasion strategies in AFP-producing gastric carcinoma: characterized by HLA-G expression and HLA class I deficiency

Alpha-fetoprotein-producing gastric carcinoma (AFPGC) is an aggressive subtype of gastric cancer characterized by a primitive cellular phenotype and poor prognosis. The tumor immunology of AFPGC remains largely unexplored. Given its embryonic-like properties, AFPGC is hypothesized to employ distinct immune evasion strategies, with the oncofetal protein human leukocyte antigen (HLA)-G-a key mediator of maternal-fetal immune tolerance-likely playing a pivotal role. To test this, we assessed the expression of HLA-G, along with other key immune evasion markers, including HLA class I (HLA-I) deficiency and PD-L1 expression, in 39 cases of AFPGC, and compared them with those of 44 Epstein-Barr virus (EBV)-positive, 57 microsatellite instability (MSI), 54 intestinal-type, and 45 diffuse-type gastric carcinomas. HLA-G expression was significantly higher in AFPGCs (71%) than in other subtypes (7-28%; P < 0.001). HLA-I deficiency (≥ 1% of tumor cells) was most prevalent in AFPGC (69%), followed by MSI tumors (56%), with lower rates in other subtypes (22-29%). PD-L1 positivity (combined positive score ≥ 5) was observed in 41% of AFPGCs, lower than in EBV-positive (77%) and MSI tumors (44%), but higher than in intestinal-type (13%) and diffuse-type (9%) carcinomas. Furthermore, CD8-positive T-cell infiltration was found to be lowest in AFPGC compared to the other subtypes. These findings suggest that AFPGC employs multiple immune evasion mechanisms, notably through increased HLA-G expression and HLA-I deficiency, likely linked to its primitive cellular phenotype and reactivation of immunogenic oncofetal antigens. Such immune evasion features may underlie the aggressiveness of AFPGC and present promising targets for immunotherapeutic interventions.