PD-L1 – PD-1 interactions limit effector Treg cell populations at homeostasis and during infection
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA773432 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16525200.fastq.gz | Fastqsanger.gz | |||
| SRR16525201.fastq.gz | Fastqsanger.gz | |||
| SRR16525172.fastq.gz | Fastqsanger.gz | |||
| SRR16525173.fastq.gz | Fastqsanger.gz | |||
| SRR16525174.fastq.gz | Fastqsanger.gz |
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Project description:PD-1 ligation delimits immunogenic responses in T cells. However, the consequences of PD-L1 ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor-antigen, microbial signals, and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (i) Binding of PD-L1 induced STAT3-dependent back-signaling in CD4+ T cells preventing activation, reducing Th1-polarization, and directing Th17-differentiation. PD-L1 signaling also induced an anergic Tbet-IFNg- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling. (ii) 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. (iii) PD-L1+ T cells engaged PD-1+ macrophages inducing an alternative M2-like program, which had crippling effects on adaptive anti-tumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.
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Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.
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Project description:Although membrane-anchored Pd-l1 has been well-studied for its engagement with PD-1 on T cells to evade anti-tumor immunity, whether Pd-l1 regulate oncogenic signaling pathways in tumor cells remains elusive. In this experiment, to further dissect roles of the K262 residue acetylation for Pd-l1 nuclear function, we profiled RNA expression of WT or K262Q mutant mouse Pd-l1 re-expressed in CT26 KO Pd-l1 cells. Methods: Total RNA fromCT26/Vector, CT26/WT or CT26 Pd-l1 KO cells was purified using Qiagen RNeasy mini kit (Qiagen) according to the manufacturer’s instructions. Library preparation and sequenceing analysis were performed by BGI-Hong Kong Co. Ltd. Conclusions: Our study indicates that Pd-l1 acetylation modification may affect its function in nuclear.
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