Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses.

ABSTRACT: The endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models, was accompanied by increased numbers of activated T cells expressing high levels of Gzma, Gzmb, Perforin, Cxcr3, and increased intratumoural levels of Cxcl9 and Cxcl10 compared to wild-type mice. Consistent with Aire's central role in T cell repertoire selection, single cell TCR sequencing unveiled expansion of several clones with high tumor reactivity. Th

SUBMITTER: Benitez AA 

PROVIDER: S-EPMC7343867 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature