Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation

Abstract

Co-inhibitory and checkpoint molecules suppress T-cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. While immune checkpoint blockade (ICB) has emerged as a successful treatment option for multiple human cancers, severe autoimmune-like side effects limit its application. Here we found the gene encoding the Peptidoglycan Recognition Protein 1 (PGLYRP1) to be highly co-expressed with co-inhibitory molecules and hypothesized that it might be a promising target for cancer immunotherapy. Indeed, genetic deletion of PGLYRP1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, the genetic deletion of PGLYRP1 strongly protected against the development of experimental autoimmune encephalomyelitis (EAE), a model of autoimmune disease in the central nervous system (CNS). Pglyrp1-deficient myeloid cells had a defect in antigen presentation and T-cell activation, indicating that PGLYRP1 might act as a proinflammatory molecule in myeloid cells during autoimmunity. Our results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.