Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion [scc]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE247058 | GEO | 2023/12/12
REPOSITORIES: GEO
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Project description:Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, the mechanism underlying this association remains inconclusive since additional factors dictate tumor aggressiveness. Here, we study the mechanisms responsible for the immune escape of tumors bearing low ITH. We compare homogeneous, genetically similar single-cell clones that are rejected vs. non-rejected after transplantation. We followed the growth of these clone-derived tumors over time using single-cell RNA sequencing and immunophenotyping. Non-rejected clones show high infiltration of tumor-associated macrophages (TAM), increased Mif expression, lower T-cell infiltration, and increased T-cell exhaustion. Mif KO led to smaller tumors and reversed these immune phenotypes, validating its role in the growth of low ITH tumors. Mif secretion by these tumor cells causes TAM infiltration, thus contributing to an immunosuppressive environment that supports aggressive growth. We validated this result in melanoma patient data, confirming that high levels of MIF distinguish aggressive from non-aggressive ITHs.
2023-12-12 | GSE247057 | GEO
Project description:Extracellular matrix (ECM) structural and compositional abnormalities are a hallmark of many cancers. Tumor associated macrophages (TAM) are considered pivotal players in mounting pro-tumoral functions; yet, their role in tumor-ECM remodeling remains largely ambiguous. Using an orthotopic murine model of colorectal cancer we defined two major CRC TAM subsets arising from Ly6Chi monocytes recruited in a CCR2-depedent manner. TAM-deficient CRC tumors established Ccr2-/- mice exhibited attenuated growth. Advanced imaging techniques revealed that the enhanced deposition, linearization and cross-linking of collagen fibers typical to tumor growth were absent in the Ccr2-/- tumors. Moreover, the Ccr2-/- tumors displayed altered ECM composition with 348 proteins that were differentially expressed in comparison with WT tumors, among them 46 were ECM related. Integrating transcriptomic and proteomic approaches we defined a TAM signature of ECM remodeling enzymes, structural and affiliated proteins. Specifically, were prominent proteins involved with the synthesis and assembly of collagen type I, IV and XIV. Finally, decellularized 3D ECM fragments extracted from WT tumors, but not from Ccr2-/- tumors or upstream healthy colon, enhanced tumor cell proliferation in vitro and tumor development in the native colonic environment. Collectively, our integrated biophysical-immunologic-omic approaches uncover new mechanistic insights of TAM-mediated remodeling of tumor ECM structure and composition.
2016-09-26 | PXD002094 | Pride
Project description:Gastro-esophageal adenocarcinomas (GEAs) are aggressive cancers and multiple trials of targeted therapies recently failed to improve survival in these tumors. Intratumor heterogeneity (ITH) is suspected to contribute to poor outcomes. Here we investigate the degree of ITH in multiple primary and metastatic regions of gastric adenocarcinoma tumours. ITH increased significantly with lymph node metastasis formation and subclonal aberrations activating the Mitogen Activated Protein Kinase (MAPK)-pathway were significantly enriched in nodal metastases. This shows that selection pressures in the lymph node ecosystem differ from those in the primary tumor, leading to evolutionary convergence of distinct tumors when they spread to lymph nodes.
2019-09-18 | GSE93583 | GEO
Project description:The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mRCC). To explore ITH in detail, multiple tumor samples were taken from the primary renal tumors of mRCC patients who were sunitinib treated (n=23) or untreated (n=23). ITH of pathological grade, DNA (using array-based comparative genomic hybridisation), RNA (Illumina Beadarray) and protein (reverse phase protein array) were evaluated. Tumor grade heterogeneity was greater in treated compared to untreated tumors (P=0.002). Unsupervised and supervised analysis, for renal cancer driver, hypoxia and stromal gene signatures, was then performed. In untreated patient tumor samples, significant ITH occurred in chromosomal aberrations, RNA and protein expression, with clustering of DNA and RNA correlating for individual patients. In unsupervised analysis sunitinib therapy was not associated with increased ITH in DNA or RNA. However there was an increase in ITH for the driver mutation and hypoxia gene signatures (DNA and RNA) as well as increasing variability of protein expression with treatment (p<0.05). Despite this variability, significant chromosomal and RNA changes to targets of sunitinib, such as VHL, PBRM1 and CAIX, occurred in the treated samples. Together these findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes. The results do not support the hypothesis that resistant clones are selected and predominate after initiation of targeted therapy; instead it appears that an initial clonal diversification occurs, supporting the hypothesis of polyclonal drug resistance. 128 samples from patients with clear cell renal cell carcinoma, including biological replicates of nephrectomy samples. Source of samples includes both biopsy and nephrectomy. DNA extracted from FFPE and fresh frozen tissue samples.
2015-05-25 | E-GEOD-67818 | biostudies-arrayexpress
Project description:The aim of this study was to examine the effect of intra-tumor heterogeneity (ITH) on detection of genes within gene expression panels (GEPs), and the subsequent ability to predict prognostic risk. Multiplexed barcoded RNA analysis was used to measure the expression of 141 genes from five GEPs (Oncotype Dx, MammaPrint, PAM50, EndoPredict, and BCI) in breast cancer tissue sections and tumor-rich cores from 71 ER positive node-negative tumors. Tumor regions with high Ki67 and/or low PR were also used to punch cores, potentially representing aggressive areas of a tumor. In addition to examining the effect of ITH on measurement of GEPs, the effect of ITH on prediction of prognosis in the Oncotype Dx assay was also assessed.
2017-02-08 | GSE79378 | GEO
Project description:Interactions between Macrophages and T-lymphocytes: Tumor
Sneaking Through Intrinsic to Helper T cell Dynamics
ROB J. DE BOER AND PAULINE HOGEWEG
Bioinformatics Group, University of Utrecht, Padualaan 8, 3584 CH Utrecht,
The Netherlands
Abstract
In a mathematical model of the cellular immune response we investigate immune
reactions to tumors that are introduced in various doses. The model represents
macrophage T-lymphocyte interactions that generate cytotoxic macrophages and
cytotoxic T-lymphocytes. In this model antigens (tumors) can induce infinitely large
T-lymphocyte effector populations because (a) effector T-lymphocytes are capable
of repeated proliferation and (b) we have omitted immunosuppression. In this
(proliferative) model small doses of weakly antigenic tumors grow infinitely large
(i.e. sneak through) eliciting an immune response of limited magnitude. Intermediate
doses of the same tumor induce larger immune responses and are hence rejected.
Large doses of the tumor break through, but their progressive growth is accompanied
by a strong immune response involving extensive lymphocyte proliferation. Similarly
a more antigenic tumor is rejected in intermediate doses and breaks through in large
doses. Initially small doses however lead to tumor dormancy. Thus although the
model is devoid of explicit regulatory mechanisms that limit the magnitude of its
response (immunosuppression is such a mechanism), the immune response to large
increasing tumors may either be (a) a stable reaction of limited magnitude (experimentally known as tolerance or unresponsiveness) or (b) a strong and ever increasing
reaction. Unresponsiveness can evolve because in this model net T-lymphocyte
proliferation requires the presence of a minimum number of helper T cells (i.e. a
proliferation threshold). Unresponsiveness is caused by depletion of helper T cell
precursors.
2019-12-11 | MODEL1912110001 | BioModels
Project description:The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mRCC). To explore ITH in detail, multiple tumor samples were taken from the primary renal tumors of mRCC patients who were sunitinib treated (n=23) or untreated (n=23). ITH of pathological grade, DNA (using array-based comparative genomic hybridisation), RNA (Illumina Beadarray) and protein (reverse phase protein array) were evaluated. Tumor grade heterogeneity was greater in treated compared to untreated tumors (P=0.002). Unsupervised and supervised analysis, for renal cancer driver, hypoxia and stromal gene signatures, was then performed. In untreated patient tumor samples, significant ITH occurred in chromosomal aberrations, RNA and protein expression, with clustering of DNA and RNA correlating for individual patients. In unsupervised analysis sunitinib therapy was not associated with increased ITH in DNA or RNA. However there was an increase in ITH for the driver mutation and hypoxia gene signatures (DNA and RNA) as well as increasing variability of protein expression with treatment (p<0.05). Despite this variability, significant chromosomal and RNA changes to targets of sunitinib, such as VHL, PBRM1 and CAIX, occurred in the treated samples. Together these findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes. The results do not support the hypothesis that resistant clones are selected and predominate after initiation of targeted therapy; instead it appears that an initial clonal diversification occurs, supporting the hypothesis of polyclonal drug resistance.
2015-05-25 | GSE67818 | GEO
Project description:Ly6Chi monocytes massively infiltrate the CRC-tumors by virtue of their CCR2 expression and further mature into Ly6CloF4/80hi CD64hiMHCII+ TAM upon tumor progression. We demonstrated that TAM-deficient tumors display impaired tumor-growth via alternation of the ECM morphology, structure and composition. Using advanced high-resolution optical imaging to visualize the tumoral-ECM macromolecule network together with transcriptomic and proteomic approaches we unraveled that TAM play critical role in the deposition, linearization and cross-linking of collagenous ECM. Remarkably, we show that cues embedded in ECM by TAM-mediated remodeling activity promote tumor cell proliferation in vitro and orthotopic tumor development in vivo. Abnormal remodeling of the extracellular matrix (ECM) structural and compositional is a hallmark of many cancers. While tumor associated macrophages (TAM) are considered pivotal players in mounting pro-tumoral functions, their role in tumor-ECM remodeling remains largely ambiguous. We found that TAM-deficient CRC tumors established in Ccr2-/- mice exhibited attenuated growth. Advanced molecular imaging revealed that the enhanced deposition, linearization and cross-linking of collagen fibers typical to tumor growth were absent in the Ccr2-/- tumors. Integrating transcriptomic and proteomic approaches we defined a TAM signature of ECM remodeling enzymes, structural and affiliated proteins involved with the synthesis and assembly of collagen. The Ccr2-/- tumors displayed altered ECM composition with 348 proteins that were differentially expressed in comparison with WT tumors, among them 46 were ECM related. Decellularized 3D ECM fragments extracted from WT tumors, but not from Ccr2-/- tumors or upstream healthy colon, enhanced tumor cell proliferation in vitro and tumor development in the native colonic environment indicating that TAM have a critical role in priming pathological ECM cues.
2016-09-15 | GSE67953 | GEO
Project description:Tumor-associated macrophages (TAMs) have immunosuppressive capacity in mouse models of cancer. Here we show that the genetic deletion of the microRNA (miRNA)-processing enzyme DICER in TAMs broadly programs them to a CD11c+MRC1â/low M1-like immunostimulatory phenotype characterized by activated interferon-γ (IFN-γ)/STAT1/IRF signaling. M1-like TAM programming fostered the recruitment of cytotoxic T-cells (CTLs), including tumor-antigen-specific CTLs, inhibited tumor growth, and enhanced the efficacy of PD1 checkpoint blockade. Bioinformatics analysis of TAM transcriptomes identified a limited set of miRNAs putatively involved in TAM programming. Re-expression of Let-7 in Dicer-deficient TAMs was sufficient to partly rescue the M2-like (protumoral) TAM phenotype and abate tumor CTL infiltration. Targeted suppression of DICER activity in TAMs may, therefore, stimulate antitumor immunity and enhance the efficacy of cancer immunotherapy. To explore the role of DICER in the development, activation and immunological functions of TAMs, we crossed homozygous LysM-Cre (Clausen et al., 1999) with Dicerlox/lox (Harfe et al., 2005) mice to obtain mice with myeloid-cell-specific Dicer1 gene deletion (LysM-Cre;Dicerâ/â, referred to as Dâ/â). These mice were then backcrossed to LysM-Cre to obtain the control LysM-Cre; Dicer+/+ mice (referred to as D+/+). Both LysM-Cre and Dicerlox/lox mutations were always homozygous in our experiment. We then inoculated Lewis lung carcinoma (LLC) cells subcutaneously (s.c.) in Dâ/â and control D+/+ mice. Once the tumors were established, we isolated by fluorescence-activated cell sorting (FACS) tumor-associated macrophages (F4/80+ cells).
2016-06-13 | E-GEOD-76356 | biostudies-arrayexpress
Project description:Glioblastomas (GBMs) are highly invasive brain tumors replete with brain- and blood-derived macrophages, collectively known as tumor-associated macrophages (TAMs). Targeting TAMs has been proposed as a therapeutic strategy but has thus far yielded limited clinical success in slowing GBM progression, due in part to an incomplete understanding of TAM function in GBM. Here, by using an engineered hyaluronic acid-based 3D invasion platform, patient-derived GBM cells, and multi-omics analysis of GBM tumor microenvironments, we show that M2-polarized macrophages stimulate GBM stem cell (GSC) mesenchymal transition and invasion. We identify TAM-derived transforming growth factor beta induced (TGFβI/BIGH3) as a pro-tumorigenic factor in the GBM microenvironment. In GBM patients, BIGH3 mRNA expression correlates with poor patient prognosis and is highest in the most aggressive GBM molecular subtype. Inhibiting TAM-derived BIGH3 signaling with a blocking antibody or small molecule inhibitor suppresses GSC invasion. Our work highlights the utility of 3D in vitro tumor microenvironment platforms to investigate TAM-cancer cell crosstalk and offers new insights into TAM function to guide novel TAM-targeting therapies.
2023-12-21 | GSE251777 | GEO