Mechanisms underlying 4-1BB agonist antibody mediated hepatotoxicity

Abstract

Abstract Agonist antibodies against the T cell costimulatory receptor 4-1BB have proven extraordinarily efficacious in the treatment of a multitude of pre-clinical murine tumors both in mono- and combination therapy settings. Although administration of α4-1BB in Phase I and II clinical trials has led to disease stabilization and partial remission in some cases of melanoma; high grade, dose limiting liver inflammation has slowed the progress of these agents toward FDA approval. We sought to uncover the mechanisms by which 4-1BB agonist antibodies trigger hepatotoxicity in hopes of discovering approaches by which the anti-tumor and hepatotoxic effects could be separated. We show that α4-1BB mediated liver damage initiates through stimulation of myeloid cells, followed by subsequent recruitment and activation of CD8 and CD4 T cells in the liver. Moreover, we show that the inflammatory cytokine IL-27 is essential in myeloid conversion of T cells into mediators of liver damage. Conversely, we show that Foxp3+ regulatory T cells are potent suppressors of 4-1BB agonist mediated hepatotoxicity; as depletion of Tregs exacerbates liver pathology. Our results go on to support the use of combination therapies in the treatment of tumor malignancies, in particular CTLA-4 blockade which may expand Tregs in the liver to ameliorate α4-1BB mediated toxicities while also amplifying anti-tumor immune responses.