Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice

• DOI: 10.1371/journal.pone.0217276
• Publication Date: 2019-05-21T17:38:33Z
• Authors: Timothy Affolter; Heather P. Llewellyn; Derek W. Bartlett; Qing Zong; Shuhua Xia; Vince Torti; Changhua Ji
• Keywords: Immune checkpoint; CTLA-4

Cancer cells harness immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) to evade control. Checkpoint inhibitors have demonstrated durable anti-tumor efficacy in human preclinical models. Liver toxicity is one of the common immune-related adverse events associated with checkpoint (CPIs) its frequency severity often increase significantly during CPI combination therapies. We aim develop a mouse model elucidate mechanisms CPI-associated liver toxicity. Co-administration CTLA-4 blocking antibody, 9D9, and/or an IDO1 inhibitor, epacadostat wild-type PD-1-/- mice (to simulate effect PD1 blockade) synergistically induced injury infiltration. Infiltrated were primarily composed CD8+ T positively hepatocyte necrosis. Strikingly, sites necrosis frequently surrounded by clusters mononuclear cells. treatments resulted increased expression genes death, leukocyte migration activation liver. In conclusion, blockade PD-1, CTLA-4, act enhance infiltration activity liver, leading death.