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Transcriptomic and proteomic characterization of cell and protein biomarkers of checkpoint inhibitor-induced liver injury [bulk RNA-seq]

ABSTRACT: Immune checkpoint inhibitors (ICI) targeting CTLA-4 and PD-1 have shown remarkable antitumor efficacy but can also cause immune-related adverse events, including checkpoint inhibitor-induced liver injury (ChILI). This multi-omic study aimed to investigate changes in blood samples from treated cancer patients who developed ChILI. PBMCs were analyzed by transcriptomic and T cell receptor sequencing (bulk and single cell), and extracellular vesicle (EV) enrichment from plasma was analyzed by mass spectroscopy proteomics. Data were analyzed by comparing the ChILI patient group to the control group who did not develop ChILI and by comparing the onset of ChILI to pre-ICI treatment baseline. We identified significant changes in T cell clonality, gene expression, and protein levels in peripheral blood mononuclear cells (PBMCs) or plasma at the time of liver injury. Onset of ChILI was accompanied by an increase in T-cell clonality. Pathway analysis highlighted the involvement of innate and cellular immune responses, mitosis, pyroptosis, and oxidative stress. Single-cell RNA sequencing revealed that these changes were primarily found in select T cell subtypes (including CD8+ effector memory cells), while CD16+ monocytes exhibited enrichment in metabolic pathways. Proteomic analysis of plasma extracellular vesicles showed enrichment in liver-associated proteins among differentially expressed proteins. Interestingly, an increase in PBMC PD-L1 gene expression and plasma PD-L1 protein was also found to be associated with onset of ChILI.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287540 | GEO | 2025/01/22

REPOSITORIES: GEO

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Project description:Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1/PD-L1 or CTLA4 have revolutionized cancer management but are associated with devastating immune-related adverse events (irAEs) including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI-myocarditis is often fulminant and is pathophysiologically characterized by myocardial infiltration of T lymphocytes and macrophages. While much has been learned regarding the role of T-cells in ICI-myocarditis, little is understood regarding the identity, transcriptional diversity, and functions of infiltrating macrophages. We employed an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, and molecular imaging. We observed marked increases in CCR2+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation expressing Cxcl9, Cxcl10, Gbp2b, and Fcgr4 that originated from CCR2+ monocytes. Importantly, a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) were found selectively in patients with ICI myocarditis compared to other forms of heart failure and myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ and CXCR3 signaling pathways. Depleting CD8+T-cells and blockade of IFN-γ signaling blunted the emergence of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis suggesting that this interaction was necessary for disease pathogenesis. Collectively, these data demonstrate that ICI-myocarditis is associated with the emergence of a specific population of inflammatory macrophages and suggest the possibility that IFN-γ blockade may serve as an effective treatment for this devastating condition.

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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Transcriptomic and proteomic characterization of cell and protein biomarkers of checkpoint inhibitor-induced liver injury [bulk RNA-seq]

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