DDI2 inhibition promotes MHC class I antigen presentation and immune checkpoint blockade efficacy in cancers

Abstract

The landscape of cancer treatments has changed dramatically over the last ten years with the use of novel checkpoint blockade immunotherapy. Even though immune checkpoint inhibitors have produced favorable objective response rates clinically, many patients have developed either primary or acquired resistance. Downregulation of the Major Histocompatibility Complex class I (MHC-I), which is critical for host defense against foreign antigens, has been observed in non-responders to those inhibitors, highlighting the importance of MHC-I antigen presentation on tumors in response to checkpoint blockades. The cytosolic protein DNA Damage Inducible 1 homolog 2 (DDI2) delivers ubiquitylated substrates to proteasomes and also has retrovirus-related proteolytic activity. We report that DDI2 constitutively antagonizes antigen presentation on MHC-I complexes. Deleting DDI2, genetically inactivating DDI2’s ubiquitin-dependent protease activity, or pharmacologically inhibiting it by using the existing FDA-approved-human immunodeficiency virus (HIV)-1 protease inhibitor, nelfinavir, increased beta-2-microglobulin (B2M) levels, surface MHC-I complexes, and antigen presentation of cytosolic proteins in many cancer cell lines. Stimulation of antigen presentation occurs after antigenic peptides enter the endoplasmic reticulum (ER) but before MHC-I complexes reach the cell surface. DDI2 inhibition increases cytotoxic T cell activation in vitro and anti-PD-1 efficacy against melanoma and pancreatic murine tumor models. Furthermore, DDI2 expression inversely correlates with activated CD8+ T-cell signatures in 80% of human solid tumors, suggesting a role for DDI2 in limiting MHC-I antigen presentation in humans. This ability of DDI2 inhibitors to enhance immune recognition and anti-PD-1 responses in mice strongly suggests that they can enhance the efficacy of immune checkpoint blockade in cancer therapy.