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Cell-intrinsic functions of PD-L1 activate autophagy and prevent cytokine-induced apoptosis

ABSTRACT: Immune checkpoint inhibitor (ICI) therapy triggers complications which are currently attributed solely to immune activation. We hypothesized that target tissue specific mechanisms also play a role and studied these mechanisms in thyrocytes. We discovered that thyroidal PD-L1 acts as a cytoprotective regulator, promoting cell survival during cytokine-induced stress. PD-L1 suppression in thyrocytes amplified IFNγ-driven stress by aberrantly activating AKT - ERK - mTORC1, inhibiting autophagy, augmenting cellular stress, and triggering apoptosis. In a mouse model of ICI-thyroiditis, anti-PD-L1 treatment triggered immune activation while promoting thyrocyte apoptosis. Mechanistically, in mice, both pharmacologic and genetic downregulation of thyroidal PD-L1 caused autophagic defects. Our findings reveal a role for PD-L1 in protecting thyroid tissue from cytokine-mediated stress and suggest that anti-PD-L1 tissue toxicity may reflect both an immune-mediated attack and intrinsic cellular vulnerability. Our data provide a broader framework for understanding ICI adverse events and for guiding the development of treatment strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE306256 | GEO | 2026/08/04

REPOSITORIES: GEO

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Project description:Background: The tumor cell-intrinsic function of programmed cell death-ligand 1 (PD-L1) is poorly understood. The roles of the intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression and the response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) were investigated. Methods: Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, ChIP-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells, and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression/or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade. Results: In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched and IL-6 expression was higher in patients with no response to ICI in PD-L1-high NSCLCs. IL-6 expression in PD-L1-high NSCLCs correlated positively with MDSCs and Tregs, but negatively with cytotoxic lymphocytes. In another ICI cohort, a higher baseline serum IL-6 level was associated with poor clinical outcome after ICI therapy. PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting tyrosine phosphatase PTP1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 on the transcription of several cytokines (IL-6, TGFβ, TNFα, IL-1β) and chemokines (CXCL1, CXCL3, CXCL8). PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSC in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing mouse lung tumors were heavily infiltrated by MDSCs with high immunosuppressive function. Treg numbers were increased while the numbers of granzyme B+ or IFNγ+ CD8 T-cells decreased. These responses were shown to be mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFNγ+ CD8 T-cells. Conclusions: The tumor-cell-intrinsic function of PD-L1 contributes to immunosuppression and tumor progression by MDSCs through the IL-6/Jak/Stat3 pathway, which may serve as therapeutic target to improve ICI efficacy in patients with PD-L1-high NSCLC.

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Cell-intrinsic functions of PD-L1 activate autophagy and prevent cytokine-induced apoptosis

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