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

Benitez, Asiel A, Khalil-Agüero, Sara, Nandakumar, Anjali, Gupta, Namita T, Zhang, Wen, Atwal, Gurinder S, Murphy, Andrew J, Sleeman, Matthew A, Haxhinasto, Sokol (July 2020) Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses. Communications Biology, 3 (1). p. 355. ISSN 2399-3642

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URL: https://www.ncbi.nlm.nih.gov/pubmed/32641748
DOI: 10.1038/s42003-020-1083-1

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. The data suggest that breakdown in central tolerance synergizes with immune checkpoint blockade in enhancing anti-tumor immunity and may serve as a model to unmask novel anti-tumor therapies including anti-tumor TCRs, normally purged during central tolerance.

Item Type: Paper
Subjects: diseases & disorders > immune system diseases > auto immune diseases
diseases & disorders > cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organism description > animal > mammal > rodent > mouse
CSHL Authors:
Communities: CSHL labs > Atwal lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 8 July 2020
Date Deposited: 07 May 2021 13:15
Last Modified: 07 May 2021 13:15
PMCID: PMC7343867
URI: https://repository.cshl.edu/id/eprint/40037

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