Macrophage phenotype in anti-PD-L1 treated MC38 tumors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA516065 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8466360.fastq.gz | Fastqsanger.gz | |||
| SRR8466370.fastq.gz | Fastqsanger.gz | |||
| SRR8466361.fastq.gz | Fastqsanger.gz | |||
| SRR8466371.fastq.gz | Fastqsanger.gz | |||
| SRR8466362.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 20 |
Similar Datasets
Project description:Checkpoint inhibitors like anti-PD1/PD-L1 have demonstrated significant therapeutic efficacy in a subset of patients partly through reinvigoration of CD8 T cells. However, their impact on myeloid cells remains largely unknown. Here we report that anti-PD-L1 treatment favorably impacts the phenotype and function of tumor macrophages by polarizing the macrophage compartment towards a more pro-inflammatory phenotype. This phenotype was characterized by a decrease in Arginase-I (ARG1) expression and an increase in iNOS, MHCII, and CD40 expression. Whole-transcriptome profiling further confirmed extensive polarization of both tumor monocytes and macrophages from a suppressive to a pro-inflammatory, immuno-stimulatory phenotype. This polarization was driven mainly through IFNγ and was associated with enhanced T cell activity. Transfer of monocytes into anti-PD-L1-treated tumor-bearing mice led to macrophage differentiation into a more pro-inflammatory phenotype, with an increase in CD8 T cells expressing granzyme B and an increase in the CD8/Treg ratio compared to control-treated mice. While in responsive tumor models anti-PD-L1 treatment remodeled the macrophage compartment with beneficial effects on T cells, both macrophage reprogramming and depletion were needed to maximize anti-PD-L1 responses in a tumor immune contexture with high macrophage burden. Our results demonstrate that anti-PD-L1 treatment can favorably remodel the macrophage compartment in responsive tumor models towards a more pro-inflammatory phenotype, mainly through increased IFNγ levels. They also suggest that directly targeting these cells with reprogramming and depleting agents may further augment the breadth and depth of response to anti-PD-L1 treatment in less responsive or more macrophage-dense tumor microenvironments. The "SAMPLE_ID" sample characteristic is a sample identifier internal to Genentech. The ID of this project in Genentech's ExpressionPlot database is NGS1772.
2019-02-12 | GSE125383 | GEO
Project description:Primary irradiated MC38 tumors and secondary MC38 non-irradiated tumors. Subcutaneous MC38 tumors in C57BL/6 mice Concurrent treatment with anti-PD-L1.
2023-10-15 | E-MTAB-13389 | biostudies-arrayexpress
Project description:Purpose: Use RNA-seq to characterize the anti-tumor immune response induced by ALPN-202 and compare to that of anti-PD-L1 treatment alone. Methods: mRNA was isolated from MC38/hPD-L1 tumors 72 hours after a single dose of ALPN-202 (n=4), anti-PD-L1 mAb (durvalumab) (n=4), or Fc control (n=4). Results: ALPN-202 treatment resulted in elevated expression of multiple T cell, NK cell, myeloid cell genes. Additionally, there was a strong increase in genes commonly associated with a proinflammatory response including cytokines, chemokines and surface markers. Conclusions: ALPN-202 treatment resulted in a strong anti-tumor immune response that was more potent than that generated by blockade of PD-L1 alone.
2022-02-10 | GSE161244 | GEO
Project description:MC38 tumors resistant to anti-PD-1 treatment (MC38-resistant) were generated through serial in vivo passaging, and global gene expression analysis was used to compare resistant and parental tumors. MC38 and MC38-resistant tumors exhibited widespread changes in global gene expression.
2021-07-22 | GSE180309 | GEO
Project description:Interleukin 6 (IL-6) is a pleiotropic cytokine with diverse roles in homeostasis, inflammation, and cancer. In multiple syngeneic mouse tumor models, we found that blockade of IL-6 signaling (using an IL6R-blocking antibody) synergized with anti-PD-L1 therapy to drive potent anti-tumor CD8 T cell responses and tumor rejection. To better characterize the cell-intrinsic effects of IL-6 signaling in tumor-reactive CD8+ T cells during anti-PD-L1 therapy, we generated mice with genetic IL6R deficiency restricted to CD8 T cells by crossing IL6R.loxp and E8i.CD8.Cre mice (CD8ΔIL6R mice). Compared to WT littermate controls, we found that CD8ΔIL6R mice had stronger respones to anti-PD-L1 therapy in terms of improved CD8 T cell function (e.g. increased production of IFNγ and TNF, measured by flow cytometry) and enhanced tumor control, suggesting that direct IL-6 signaling in CD8 T cells is sufficient to impair anti-tumor immunity. In this study we aimed to characterize the phenotype of IL6R-deficient CD8 T cells in more detail via whole-transcriptome profiling. CD8ΔIL6R and WT littermates were implanted with MC38 tumors in the right flank; when tumors reached ~150mm3 in volume, animals were randomized to isotype control or anti-PD-L1 treatment. CD8 T cells were FACS-purified from tumor tissue 7 days later and profiled by bulk RNAseq. Compared to cells from WT mice, CD8 T cells from CD8ΔIL6R mice showed increased expression of interferon-driven gene signatures, increased expression of cell cycle genes, and increased expression of genes critical for oxidative phosphorylation. In contrast, WT cells had higher expression of genes associated with naive and memory precursor cells. Thus, IL-6 signaling in tumor-reactive CD8 T cells limits their capacity to differentiate into potent anti-tumor effectors.
2022-11-04 | GSE199047 | GEO
Project description:Dendritic cells (DCs) express high levels of PD-L1 in the tumor microenvironment and draining lymph nodes. Here, we explore the roles of PD-L1 signaling during immunogenic chemotherapy. DC-conditional PD-L1 knockout mice were inoculated with MC38-OVA tumors and treated with doxorubicin. T cells were isolated from draining lymph node for single cell RNA sequencing.
2024-09-23 | GSE223509 | GEO
Project description:Cancer immunotherapy has focused on inhibitors of checkpoint proteins, such as Programmed Death Ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, we assumed that intrinsic and microenvironmental factors are involved. Among all non-immunological signaling pathways we surveyed in patients’ datasets, EGFR signaling best associated with high PD-L1. Correspondingly, active EGFRs stabilized PD-L1’s transcripts and depleting PD-L1 severely inhibited EGFR-driven tumorigenicity and metastasis in mice. The underlying mechanisms involve recruitment of phospholipase C-g1 (PLC-g1) to a cytoplasmic motif of PD-L1, which enhances PLC-g1 activation by EGFR. Once stimulated, PLC-g1 activates calcium flux, RHO GTPases and protein kinase C, which promotes an aggressive phenotype. Furthermore, anti-PD-L1 antibodies can inhibit these intrinsic functions of PD-L1. Our results portray PD-L1 as a molecular amplifier of EGFR signaling and lay the foundation for understanding resistance of EGFR+ tumors to immunotherapy.
2021-04-08 | GSE171650 | GEO
Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
2015-05-01 | E-GEOD-65041 | biostudies-arrayexpress
Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
2024-10-22 | GSE279750 | GEO
Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.
2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress