ANGPTL2-mediated epigenetic repression of MHC-I in tumor cells accelerates tumor immune evasion.

Loss or downregulation of major histocompatibility complex class I (MHC-I) contributes to tumor immune evasion. We previously demonstrated that angiopoietin-like protein 2 (ANGPTL2) promotes tumor progression using a Xp11.2 translocation renal cell carcinoma (tRCC) mouse model. However, molecular mechanisms underlying ANGPTL2 tumor-promoting activity in the tRCC model remained unclear. Here, we report that ANGPTL2 deficiency in renal tubular epithelial cells slows tumor progression in the tRCC mouse model and promotes activated CD8 T cell infiltration of kidney tissues. We also found that Angptl2-deficient tumor cells show enhanced interferon γ (IFNγ)-induced expression of MHC-I and increased susceptibility to CD8 T cell-mediated anti-tumor immune responses. Moreover, we provide evidence that the ANGPTL2-α5β1 integrin pathway accelerates polycomb repressive complex 2 (PRC2)-mediated repression of MHC-I expression in tumor cells. These findings suggest that ANGPTL2 signaling in tumor cells contributes to tumor immune evasion and that suppressing that signaling in tumor cells could serve as a potential strategy to facilitate tumor elimination by T cell-mediated anti-tumor immunity.