B7-H4 NON-IMMUNOLOGICAL ROLE IN INCREASING ENDOMETRIAL CANCER AGGRESSIVENESS

Introduction Endometrial cancer (EC) represents the most diagnosed gynaecological malignancy. Based on histopathology and clinical behavior, EC is divided in estrogen-dependent endometrioid type I and the most aggressive estrogen-independent non-endometrioid type II. Despite treatment options are used successfully for Type I subtype, limited options remain if tumors relapse or metastasize. Overall, the 5-year overall survival rate for high stage cancer is around 15%-17% and mortality has increased by approximately 1.4% per year. For these reasons, identify a novel biological marker could help to design a better therapeutic approach target for patients with advanced or recurrent disease. Its high immunogenicity and increased CD3+ and CD8+ tumor-infiltrating lymphocytes, makes it an ideal target for immunotherapy. B7 family, a cell-surface protein ligands, binding to receptors on lymphocytes, is intensely studied for their potential clinical impact in human malignancies. Its member, B7-H4, play a role in inhibition of both CD4+ and CD8+ T cell. Additionally, its expression has been found in different cancer types and associated with poor clinical outcomes. Material and Methods Analysing TCGA data, it has been performed a molecular profiling in a cohort of 507 patients, both types I and II: Using RT-PCR and western blot B7-H4 expression was analyzed in different primary human EC cell lines. In vitro, it was investigated the cell autonomous role of B7-H4 in controlling cell survival and migration. Results and Discussions Preliminary results show that B7-H4 is more expressed in Type II EC patients compared with Type I. Similarly, it has been found in EC primary cell lines with a high expression in the most aggressive mixed type I/II cells. Additionally, patients with high B7-H4 expression show a shorter disease-free survival. These findings support a possible role of B7-H4 in increasing the aggressiveness of cancer cells. Furthermore, silenced B7-H4 cells show a reduction in migration capability and cell proliferation. To support B7-H4 immunological role, preliminary data obtained by in vitro co-culture with macrophages and Natural Killer cells, showed that B7-H4-silenced cells influence immune cells recognition. Conclusion These preliminary results may suggest that B7-H4 could have an additional non-immunological role supporting EC malignancy and could be useful as prognostic marker and potential new biological target for immunotherapy.