FATS deficiency in mice limits melanoma progression via converting the tumor immune microenvironment to an anti-tumor state

Abstract

Abstract C10orf90 is a newly identified common fragile sites gene named fragile-site associated tumor suppressor (FATS) according its tumor suppressive function in FATS overexpressive cancer cell lines. However, our FATS knockout mice data suggested that FATS may service as an important immune regulator. In this study, we found that FATS deficiency in mice can significantly inhibit the tumor incidence and growth of melanoma implanted with B16 cells. In addition, FATS deficient mice obviously increased the numbers and frequency of tumor suppressor cells CD3+ T cell, γδT and NK cells, and decreased tumor promoter cells PMN-MDSC and Treg cell, in tumor tissues. Notably, DCs which play a key role in immune response initiation were dramatically increased in tumor tissues of the FATS deficiency mice. Furthermore, IL-2 which is crucial to the activation of T cells, significantly increased in serum of the FATS deficiency mice compared with the WT mice, meanwhile, other cytokines, such as IFN-γ and IL-12 were increased as well. Importantly, FATS deficiency increased the expression of IFN-γ in CD8+ T cells and CD4+ T cells and facilitated the activation of these T cells separated from the mice tumor tissues. Also, perforin and granzyme, the pivotal effector molecules in tumor cytotoxicity, raised in the CD8+ T cells from the melanoma tissues of FATS deficiency mice. Consistently, in the ex vitro study, DC separated from FATS deficiency mice with melanoma could significantly promote the proliferation and activation of T cells. These results demonstrate the inhibitory effect of FATS deficiency on the progression of melanoma via regulating tumor immune microenvironment and suggest that FATS could be a potential immune therapeutic target for malignant tumors.