KIRA6 abrogates the generation of myeloid-derived suppressor cells and overcomes resistance to anti-PD-1 therapy

Immune checkpoint blockade (ICB) therapy is one of the cornerstones of cancer treatment regimens in a broad range of cancers nowadays, but the overall response rates remain low as a result of alternative immunosuppressive immune cells, such as myeloid-derived suppressor cells (MDSCs). Therefore, it is unmet need to target MDSCs in the tumor microenvironment to achieve better outcome of ICB therapy. Inositol-requiring enzyme 1a (IRE1a) is identified as a key regulator for generation of MDSC. Here, we evaluated the potential of KIRA6, an inhibitor for IREa kinase activity and RNase activity, to abrogate MDSC mediated immune suppression and improve outcome of ICB therapy. Overall design: 4T1 cells were plated overnight in complete RPMI 1640 medium and then replaced with fresh culture medium with Vehicle or KIRA6 (1 µmol/L). Cells were cultured for 4 hours before RNA sample collection with TRIzol.