Immune evasion from macrophages by NEAT1-induced CD24 in liver cancer

The limited efficacy of immune checkpoint inhibitors in hepatocellular carcinoma (HCC) can arise from the involvement of immunosuppressive cells, such as macrophages. In the present study, we found that the long noncoding RNA NEAT1, particularly its short isoform (NEAT1v1) induced the expression of CD24, which is known as an immune checkpoint molecule for macrophages. Mechanistically, NEAT1v1 sponged miR-320a-3p to upregulate the transcription factor SP1, which in turn, activated CD24 transcription. A spheroid co-culture of primary or THP-1-derived macrophages with HCC cells revealed that NEAT1v1 suppressed M1 marker expression and phagocytic activity in macrophages. In a syngeneic subcutaneous model of HCC, Neat1v1 increased the tumor infiltration of M2-like macrophages and induced resistance to anti-Pd-1 antibody, while combination of the anti-Pd-1 and anti-Cd24 antibodies significantly suppressed the tumor growth. Finally, NEAT1, SP1, and CD24 expression increased in tumor tissues from patients with HCC, compared to adjacent normal tissues, whereas miR-320a-3p was significantly downregulated. Moreover, plasma NEAT1 cell-free RNA was significantly decreased after therapeutic intervention. Taken together, NEAT1v1 protects HCC cells from macrophages by sending a "Don't Eat Me" signal via CD24, and is therefore, a potential target molecule for the treatment and diagnosis of HCC.