Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma
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ABSTRACT:
PROVIDER: PRJNA976204 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24735943.fastq.gz | Fastqsanger.gz | |||
| SRR24735944.fastq.gz | Fastqsanger.gz | |||
| SRR24735945.fastq.gz | Fastqsanger.gz | |||
| SRR24735946.fastq.gz | Fastqsanger.gz | |||
| SRR24735947.fastq.gz | Fastqsanger.gz |
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Project description:Introduction Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. Methods HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. Results Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status. Conclusion Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.
2023-05-30 | GSE233405 | GEO
Project description:IntroductionImmune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC.MethodsHCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses.ResultsImmunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status.ConclusionImmunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.
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Project description:We previously identified and validated a pre-treatment peripheral blood biomarker, characterized by a high frequency of LAG-3+ lymphocytes, that predicts resistance in patients receiving anti-PD-1 immune checkpoint blockade. To better understand the mechanism of aPD-1 resistance and select rational therapies to overcome resistance, we identified murine tumor models with a high LAG-3+ lymphocyte frequency (LAG-3hi), which were resistant to aPD-1 therapy, and LAG-3lo murine tumor models that were aPD-1 sensitive, recapitulating the predictive biomarker we previously described in patients. As we hypothesized, LAG-3hi tumor-bearing mice were sensitive to aPD-1+aLAG-3 therapy and the benefit of combination therapy was CD8+ T cell-dependent. Unexpectedly, the benefit of combination therapy was enhanced in LAG-3hi (but not LAG-3lo) mice with depletion of CD4+ T cells. Furthermore, responses to aPD-1+aLAG-3 significantly correlated with T regulatory cell (Treg) phenotypic plasticity in LAG-3hi mice, suggesting a specific role for Tregs in the mechanism of response to this combination. Using Treg fate tracking Foxp3GFP-Cre-ERT2 x ROSAYFP reporter mice we demonstrate that expanded populations of unstable Tregs correlate with response to combination therapy in LAG-3hi mice. Complementing this preclinical data, an increased proportion of unstable Tregs also significantly correlated with higher response rate and improved survival after aPD-1+aLAG-3 therapy in a cohort of patients with metastatic melanoma (n=117). These data indicate that Treg phenotypic plasticity is a key mechanism in aPD-1+aLAG-3 responsiveness, which may represent both a novel biomarker to aid patient selection and a rationale therapeutic target to expand benefit for a subset of PD-1 refractory patients.
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Project description:An immunohistochemical atlas of necroptotic pathway expression
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Project description:We report the application of conventional ChIP-seq analysis for LAG-1 chromatin state in germline. We identified 137 genes putatively regulated by LAG-1 that's overlapped by three independent biological replicates. These genes included previously known targets lst-1, sygl-1, and mir-61/250.
2020-02-17 | GSE144223 | GEO
Project description:Purpose: Ultilize Next Generation Sequencing to identify genes that are activated or repressed by LAG-1 (following auxin treatment to specifically deplete LAG-1 in C. elegans germline). The list of genes generated from RNA-seq identify primary and secondary targets of LAG-1 in C. elegans germline stem cells. Methods: RNA isolated from hand dissected C. elegans germline tumor (one day old adult animals) were used for RNA-seq library. Results: two genes (lst-1 and sygl-1) were identified as primary target for LAG-1 (2 hours auxin treatment); five additional genes are identified as secondary targets of LAG-1 based on their RNA accumulation depend on primary targets lst-1 and sygl-1 activity (4 hours auxin treatment). 94 genes are identified to be activated by LAG-1 (48 hours auxin treatment) from 4 biological replicates with the following criteria: gene counts per million greater than 2.0; fold of change greater than 2.0; false discovery rate (FDR) <0.05. Conclusions: lst-1 and sygl-1, two previously reported genes, are identified as primary transcriptional target for LAG-1 in C. elegans germline stem cells.
2020-02-17 | GSE144227 | GEO
Project description:Fractionation RNAseq in conjunction with Illumina TRUseq method
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Project description:We report the application of conventional ChIP-seq analysis for LAG-1 chromatin state in whole animals. We identified 76 genes putatively regulated by LAG-1 that's overlapped by two independent antibodies (FLAG ab and GFP ab). These genes including previously known targets lst-1, sygl-1, and mir-61/250, supporting the success of the assay.
2020-02-17 | GSE144225 | GEO
Project description:In chronic infections, sustaining the CD4 T cell responses is crucial for pathogen clearance. The expression of inhibitory receptors such as LAG-3 or Lymphocyte activation gene 3 is usually associated with immune suppression and T cell exhaustion. However, LAG-3 also serves as an immune checkpoint molecule and is implicated in proliferation control and cell survival. In this study, we have utilized a mouse model of visceral leishmaniasis (VL), to characterize a subset of LAG-3- and CXCR5-expressing CD4 T cells. These LAG-3+CXCR5+PD-1lo/int CD4 T cells exist in naïve mice, they expand during VL, and are antigen specific. Importantly, the RNAseq analysis showed that these cells highly express gene signatures associated with self-renewal capacity, indicating that these cells might act as progenitors. Additionally, upon adoptive transfer into Rag1-/- mice followed by challenge with Leishmania donovani, these LAG-3+CXCR5+ PD-1lo/int CD4 T cells gave rise to different types of T effector and regulatory subsets, demonstrating their differentiation potential. These cells were also observed in mice infected with LCMV clone-13 and Heligmosomoides polygyrus bakeri. In summary, we propose that these LAG-3+CXCR5+ PD-1lo/int CD4 T cells that exhibit progenitor-like capacities could be implicated in maintaining CD4 T cell responses in chronic infections.
2024-02-13 | GSE255333 | GEO
Project description:Regulatory T cells (Tregs) are known to exert a critical role in self tolerance. This subset of cells is also implicated in immune evasion mechanisms operated by cancer cells. In humans, it is known that Tregs are a heterogeneous population that includes different subsets of T cells with different phenotype, differentiation state and presumably exerting their suppressor activity with different modalities. We have provided data showing that a subset of human CD4+ Tregs (CD25hiFoxp3+) expressing the Lymphocytes Activation Gene 3 (LAG-3) molecule is amplified in melanoma invaded lymph nodes as compared with their tumor free counterpart, and these cells are endowed with enhanced suppressive functions (Camisaschi et al., J Immunol 2010). To gain insights into the phenotype, functional features and specificity of this population of Tregs expressing LAG-3, we performed microarrays to obtain gene expression profiles of LAG-3+ and LAG-3- Tregs.
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