Granulomatous inflammatory responses are elicited in the liver of PD-1 knockout mice by de novo genome mutagenesis.

Abstract

Introduction: Programmed death-1 (PD-1) is a negative regulator of immune responses. Upon deletion of PD-1 in mice, symptoms of autoimmunity developed only after they got old. In a model experiment in cancer immunotherapy, PD-1 was shown to prevent cytotoxic T lymphocytes from attacking cancer cells that expressed neoantigens derived from genome mutations. Furthermore, the larger number of genome mutations in cancer cells led to more robust anti-tumor immune responses after the PD-1 blockade. To understand the common molecular mechanisms underlying these findings, we hypothesize that we might have acquired PD-1 during evolution to avoid/suppress autoimmune reactions against neoantigens derived from mutations in the genome of aged individuals.

Methods: To test the hypothesis, we introduced random mutations into the genome of young PD-1^-/- and PD-1^+/+ mice. We employed two different procedures of random mutagenesis: administration of a potent chemical mutagen N-ethyl-N-nitrosourea (ENU) into the peritoneal cavity of mice and deletion of MSH2, which is essential for the mismatch-repair activity in the nucleus and therefore for the suppression of accumulation of random mutations in the genome.

Results: We observed granulomatous inflammatory changes in the liver of the ENU-treated PD-1 knockout (KO) mice but not in the wild-type (WT) counterparts. Such lesions also developed in the PD-1/MSH2 double KO mice but not in the MSH2 single KO mice.

Conclusion: These results support our hypothesis about the physiological function of PD-1 and address the mechanistic reasons for immune-related adverse events observed in cancer patients having PD-1-blockade immunotherapies.