Single-cell characterization of anti-LAG3+anti-PD1 treatment in melanoma patients
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PROVIDER: EGAS00001005580 | EGA |
REPOSITORIES: EGA
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Project description:Combined nivolumab (anti-PD1) and relatlimab (anti-LAG3) have shown enhanced effectiveness in melanoma patients. However, how these two receptors work together to hinder anti-tumor immunity remains unclear. Our study demonstrates that PD1/LAG3-deficient CD8+ T cells with more effectively clearing tumors and survive longer in melanoma mouse models. These PD1/LAG3-deficient CD8+ T cells have unique transcriptional profiles, broad TCR clonality, and enriched effector-like and interferon-responsive genes, leading to increased IFN gamma release indicating functionality. PD1 and LAG3 together drive T cell exhaustion, with a significant impact on TOX modulation. Mechanistically, autocrine IFN gamma signaling is crucial for enhancing anti-tumor immunity in PD1/LAG3-deficient CD8+ T cells, providing insights into the enhanced efficacy of combined PD1 and LAG3 targeting.
2024-08-07 | GSE262740 | GEO
Project description:We evaluated blood samples from 6 patients with metastatic melanoma treated with anti-LAG3+anti-PD1 (160+480 mg) in a phase I trial (NCT01968109) using single-cell RNA and T cell receptor (TCR) sequencing (scRNA+TCRαβ-seq, 10X 5') combined with other multiomics profiling (flow, cytokine, TCRb-seq) from a larger cohort of 40 patients. This data set include three time points, including baseline, 1 month, and 3 month. The sorting is CD45+.
2023-02-03 | E-MTAB-12733 | biostudies-arrayexpress
Project description:TILs were extracted from two ccRCC patients treated with (Nivolumab) anti-PD1, one was responsive to treatment, the other non-responsive. IgG4 staining was used to separate cells into anti-PD1 bound and unbound, the samples then underwent paired scRNA and scTCR sequencing on the 10x Genomics platform.
| EGAS00001005640 | EGA
Project description:Background & Aims: Immune checkpoint inhibitors combined with anti-angiogenic agents produces benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. Approach & Results: C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumours received cabozantinib, anti-PD1, their combination or placebo. Tumour and blood samples were analysed by flow cytometry, immunohistochemistry, transcriptome and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer PDX model. Transcriptomic data from three human HCC cohorts (Cohort 1: n=167, Cohort 2: n=57, TCGA: n=319) were used to cluster patients according to neutrophil features, and assess their impact on survival. The combination of cabozantinib and anti-PD1 showed increased anti-tumour efficacy compared to monotherapy and placebo (P<0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced CD8+PD1+ T cell proportions in the tumour, while the combination with anti-PD1 further stimulated both effects and significantly decreased T regulatory cell infiltration (all P<0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P<0.01) and memory/effector T cells (P<0.05), while lowering the neutrophil-to-lymphocyte ratio (P<0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumour enrichment in neutrophil features observed with the treatment combination was linked to less proliferative phenotypes, and well-differentiated HCC with better prognosis. Neutrophil recruitment in both humans and mice was linked to CXCR2 ligands and CXCL12 (P<0.05). Conclusions: Cabozantinib in combination with anti-PD1 enhanced anti-tumour immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favours this approach for the treatment of HCC.
2022-06-15 | GSE174570 | GEO
Project description:Background & Aims: Immune checkpoint inhibitors combined with anti-angiogenic agents produces benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. Approach & Results: C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumours received cabozantinib, anti-PD1, their combination or placebo. Tumour and blood samples were analysed by flow cytometry, immunohistochemistry, transcriptome and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer PDX model. Transcriptomic data from three human HCC cohorts (Cohort 1: n=167, Cohort 2: n=57, TCGA: n=319) were used to cluster patients according to neutrophil features, and assess their impact on survival. The combination of cabozantinib and anti-PD1 showed increased anti-tumour efficacy compared to monotherapy and placebo (P<0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced CD8+PD1+ T cell proportions in the tumour, while the combination with anti-PD1 further stimulated both effects and significantly decreased T regulatory cell infiltration (all P<0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P<0.01) and memory/effector T cells (P<0.05), while lowering the neutrophil-to-lymphocyte ratio (P<0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumour enrichment in neutrophil features observed with the treatment combination was linked to less proliferative phenotypes, and well-differentiated HCC with better prognosis. Neutrophil recruitment in both humans and mice was linked to CXCR2 ligands and CXCL12 (P<0.05). Conclusions: Cabozantinib in combination with anti-PD1 enhanced anti-tumour immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favours this approach for the treatment of HCC.
2022-06-15 | GSE174770 | GEO
Project description:Cancers only develop if they escape immunosurveillance, and the success of cancer immunotherapies relies in most cases on their ability to restore effector T-cell functions, particularly IFN-γ. Revolutionizing the treatment of many cancers, immunotherapies targeting immune checkpoints such as PD1 may increase survival and cure patients. Unfortunately, although immunotherapy has greatly improved the prognosis of patients, not all respond to anti-PD1 immunotherapy, making it crucial to identify alternative treatments that could be combined with current immunotherapies to improve their effectiveness. Here, we show that iron supplementation significantly boosts T-cell responses in vivo and in vitro. Such a phenomenon could be the consequence of a metabolic reprogramming of T cells by iron. The "adjuvant" effect of iron results in a strong slowdown of tumor-cell growth after tumor-cell line transplantation in mice. Specifically, our results suggest that iron supplementation promotes anti-tumor responses by increasing IFN-γ production by T cells. In addition, iron supplementation considerably improves the efficacy of anti-PD1 cancer immunotherapy in mice. Finally, our study suggests that, in cancer patients, the quality and efficacy of the anti-tumor response following anti-PD1 immunotherapy may be modulated by plasma ferritin levels. In summary, our results suggest the benefits of iron supplementation on the reactivation of anti-tumor responses and support the relevance of a fruitful association between immunotherapy and iron supplementation.
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Project description:Patients with advanced melanoma have shown an improved outlook after receiving anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapy efficacy remains a major challenge. Here, our findings show significantly higher abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanomas via STAT1/3. We also found that supplementation with α-KG significantly increased methylcytosine dioxygenase TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 had been recognized and stabilized in PD-L1 promoter to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that the TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, we provide a novel insight into α-KG's function in melanoma anti-PD1 treatment and supplement of α-KG is a novel promising strategy to improve the efficacy of anti-PD1 therapy.
2023-03-08 | GSE223110 | GEO
Project description:NIPIRESCUE is a national, single-arm, open-label phase II study. The study aims to evaluate the clinical activity of nivolumab and ipilimumab in patients with MSI/dMMR mCRC resistant to anti-PD1 monotherapy and previously treated with fluoropyrimidine, oxaliplatine, irinotecan, and anti- vascular endothelial growth factor (VEGF) or anti- epidermal growth factor receptor (EGFR) therapy.
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Project description:Treatment with immunotherapy, particularly immune checkpoint blockade, can lead to benefit in the clinical setting. However, many preclinical and clinical studies suggest that resistance to anti-PD1 treatment frequently occurs, resulting in tumor relapse and treatment failure in cancer including hepatocellular carcinoma (HCC) patients. In this study ,10 HCC patients were treated with anti-PD1, and the biopsy samples before treatment were used for 289 nanostring panel RNA sequencing to compare responding and non-responding tumors to find possible pretreatment biomarkers or targets of the anti-PD1 therapy response
2022-06-20 | GSE198190 | GEO
Project description:Despite remarkable achievements, majority of hepatocellular carcinoma (HCC) patients fail to respond to anti-PD1 therapy. Here, we showed that ZFP64 was frequently upregulated in HCC tissues of anti-PD1 resistance patients. Elevated ZFP64 levels triggered tumor progression and induced an immunosuppressive microenvironment. Mechanistically, ZFP64 transcriptionally activated colony-stimulating factor 1 (CSF1) by directly binding to its promoter, and secreted CSF1 driving the shift of macrophages into an alternatively activated phenotype. Importantly, the PKCα was revealed to phosphorylate ZFP64 at S226, resulting in its nuclear translocation to transcribe the CSF1 gene. Particularly, we proposed firstly that the PKCα/ZFP64/CSF1 axis was a critical pathway in fostering immune evasion and anti-PD1 tolerance and inhibiting this axis with lenvatinib or Gö6976 surmounted the anti-PD1 resistance in HCC. Our study indicates that the ZFP64 is an emerging indicator in predicting anti-PD1 efficacy, and reveals the PKCα/ZFP64/CSF1 axis is a suitable target for anti-PD1 combination therapy in HCC.
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