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

• Published in: PloS one Vol. 14; no. 5; p. e0217276
• Main Authors: Affolter, Timothy, Llewellyn, Heather P, Bartlett, Derek W, Zong, Qing, Xia, Shuhua, Torti, Vince, Ji, Changhua
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21-05-2019; Public Library of Science (PLoS)
• Subjects: Animal models; Animal welfare; Animals; Antibodies; Anticancer properties; Apoptosis; B cells; Biochemistry; Biology and Life Sciences; Blocking antibodies; Cancer; Cancer cells; Cancer treatment; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell activation; Cell death; Complications and side effects; Computer simulation; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 protein; Cytotoxicity; Disease Models, Animal; Drug dosages; Female; Gastroenterology; Gene expression; Genes; Hepatitis; Hepatocytes; Hepatocytes - pathology; Hepatology; Humans; Immune checkpoint; Immune system; Immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Infiltration; Inflammation; Inhibitors; Ipilimumab; Ipilimumab - administration & dosage; Laboratory animals; Leukocyte migration; Leukocytes; Liver; Liver - immunology; Liver - injuries; Liver - pathology; Liver cancer; Liver diseases; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Metastases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mortality; Necrosis; Nivolumab - administration & dosage; Oximes - administration & dosage; Pathology; PD-1 protein; Product safety; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - deficiency; Programmed Cell Death 1 Receptor - genetics; Proteins; R&D; Research & development; Research and Analysis Methods; Risk factors; Safety research; Sulfonamides - administration & dosage; T cell receptors; T cells; Toxicity; Toxicology; Tryptophan 2,3-dioxygenase; Tumors; La Jolla California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0217276

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