PCSK9 inhibition potentiates cancer immune checkpoint therapy

Despite its great success, cancer immune therapy is still of limited efficacy in the majority of cancer patients(1,2). Many efforts are underway to identify novel approaches to enhance immune checkpoint therapy(3–5). Here we show that inhibition of PCSK9, a key protein in regulating cholesterol metabolism(6–8), can boost tumor response to immune checkpoint therapy, albeit through a mechanism independent of its cholesterol regulating functions. Deletion of the PCSK9 gene in murine cancer cells significantly attenuated or prevented their growth in mice in a cytotoxic T-cell-dependent manner. It also enhanced the efficacy of anti-PD1 immune checkpoint therapy significantly. Furthermore, clinically approved PCSK9-neutralizing antibodies could synergize with anti-PD1 therapy in suppressing tumor growth in murine tumor models. PCSK9 inhibition, either through genetic deletion or PCSK9 antibodies, caused a significant increase in tumor cell surface major histocompatibility protein class I (MHC I) expression, which promoted robust intratumoral infiltration of cytotoxic T-cells. Mechanistically, we discovered that PCSK9 could disrupt the recycling of MHC I to the cell surface by promoting its relocation and degradation in the lysosome through physical association. Taken together, we believe PCSK9 inhibition is a promising strategy to enhance cancer immune checkpoint therapy.