PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer.

Nature Immunology
Brian DiskinGeorge Miller

Abstract

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.

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Methods Mentioned

BETA
fluorescence microscopy
flow cytometry
RNA-seq
scRNA-seq
Protein Assay
PCR
chip
transfection

Software Mentioned

NIS
Elements AR
Picard RnaSeqMetrics
DESeq2 R
Illumina bcl2fastq
GraphPad Prism
R package GOplot
InForm
STAR aligner
GSEA

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