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: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: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.
2024-04-02 | GSE262545 | 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: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: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: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.
| 2717352 | ecrin-mdr-crc
Project description:Background: Cancer Immunotherapy with cytokines has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune activation. Here, we addressed these challenges by engineering a fusion protein of a single, potency-reduced, IL-15 mutein and an anti-PD1 antibody (αPD1-IL15m). This immunocytokine is designed to deliver PD1-mediated avidity-driven IL-2/15 receptor stimulation preferentially to PD1-positive tumor-infiltrating lymphocytes (TILs) while reducing the natural preference of IL-15 for circulating peripheral NK or T cell Methods: We isolated human lymphocytes from resected hepatocellular carcinoma tissue and cultured these tumor-infiltrating lymphocytes (TILs) in vitro in the presence or absence of an PD1-targeted IL15 mutein, anti-PD1 antibody or IL-15 agonist. After 9 days, CD4+ TILs and CD8+ TILs were sorted by FACS and RNA of 3,000 to 150,000 cells was isolated. Results: The PD1-IL15 fusion cytokine enhanced pro-survival, proliferation and activation pathways in tumor-infiltrating CD4+ and CD8+ cells compared to untreated controls as well as to the combined treatment of single agents (anti-PD1 antibody and IL-15 agonist)
2021-05-25 | GSE157893 | GEO
Project description:Gene expression profile at single cell level of human TILs treated with PD1-TIM3, PD1-LAG3, anti-PD1 or control isotype.
| PRJNA858410 | ENA