![]() ![]() A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. ![]() ![]() It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism 6, 7, 8-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9’s cholesterol-regulating functions. Many efforts are therefore underway to identify new approaches that enhance such immune ‘checkpoint’ therapy 3, 4, 5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Despite its success in achieving the long-term survival of 10–30% of treated individuals, immune therapy is still ineffective for most patients with cancer 1, 2. ![]()
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