PD-1-targeted immunotherapy in NASH-triggered liver cancer induces pro-tumorigenic environment through CD8+PD-1+ T-cells
UID: 10665
- Description
- Summary from the GEO: "Whereas some cancer types (e.g. melanoma) can be efficiently treated with immunotherapy, others lack measurable positive effects (e.g. PDAC ). Moreover, stratification of responders/non-responders is only possible in some cancer types (e.g. melanoma). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, and represents a potential cancer entity for successful immunotherapy. Here, we investigated NASH -triggered HCC in the context PD-1-targeted immunotherapy. Using flow cytometry, single cell RNA sequencing, immunohistochemistry and mass spectrometric analyses, we found a progressive increase of CD8+PD-1+ effector T-cells with a unique profile of exhaustion and activation markers rising with murine and human NASH severity. Notably, late-stage HCC treatment with PD-1-targeted immunotherapy enhanced hepatic carcinogenesis in mice. To dissect potential mechanisms of action during tumor-initiation and -progression we analyzed the effects of PD-1-targeted immunotherapy at HCC initiation. Anti-PD-1 treatment induced a pro-tumorigenic environment, enhanced necro-inflammation and increased NAFLD -activation score (NAS), leading to increased liver cancer incidence, tumor number and nodule size. In contrast, anti-CD8 treatment reduced NAS and abrogated the development of liver cancer, thus identifying CD8+PD-1+ T-cells as drivers of liver cancer in NASH-triggered HCC. Increased apoptotic signaling, STAT3 phosphorylation and hepatic proliferation were detected in intra-tumoral liver tissue upon PD-1-targeted immunotherapy. In line, PD-1-/- mice challenged with a NASH diet displayed early onset of hepatocarcinogenesis, corroborating the pro-tumorigenic role of absent or reduced PD-1. Mechanistically PD-1-targeted immunotherapy increased hepatic abundance of CD8+PD-1+Tox+CXCR6+CD8+PD-1+TNF+CD39+Gzmb+ T cells found in NASH livers, creating a pro-tumorigenic liver environment."
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Access via GEO
Plain Text Data of expression profiling by high throughput sequencing
Accession #: GSE144635Access via SRARNA Sequence reads for 37 samples
Accession #: SRP246364Access via BioProjectAdditional information about overall initiative.
Accession #: PRJNA604245 - Access Restrictions
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Free to All
- Access Instructions
- The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
- Associated Publications
- Data Type
- Equipment Used
- Software Used
- Dataset Format(s)
- Plain Text, SRA, TAR
- Data Tool(s)
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RNA Seq
- Dataset Size
- 20 MB (TAR of TXT), 13.57 (SRA)
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