Gene expression profiles of microdissected tumor epithelium and stroma from TN breast tumors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE88715 | GEO | 2019/02/22
REPOSITORIES: GEO
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Project description:Engaging the immune system promises to be key for optimal cancer therapy, especially in hard-to-treat disease such as triple-negative breast cancer (TNBC). However, the immune microenvironment remains poorly understood. Using gene expression based on laser capture microdissection, we identify three distinct tumor microenvironments associated with CD8+ T cell localization patterns and outcome in TNBC. An immunoreactive microenvironment is defined by granzyme B-positive CD8+ T cell infiltration, a type I interferon signature, tumor expression of PD-L1 and good outcome. In contrast, tumors with an immune-cold microenvironment display restriction of CD8+ T cells to tumor margins, elevated tumor expression of the immunosuppressive marker B7-H4, a signature of desmoplastic stroma and poor outcome. A third distinct immunomodulatory microenvironment associated with poor outcome is enriched for IL-17-producing cells and neutrophils, as well as stroma-restricted localisation of CD8+ T cells. These distinct immune microenvironments have implications for TNBC patient stratification for current and future therapies.
2019-02-22 | GSE88847 | GEO
Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8
T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.
2023-06-16 | MSV000092193 | MassIVE
Project description:Breast cancer is an extremely heterogeneous disease. This heterogeneity can be observed at multiple levels, including gene expression, chromosomal aberrations, and disease pathology. A clear understanding of these differences is important since they impact upon treatment efficacy and clinical outcome. Many studies have shown that the tumor microenvironment also plays a critical role in cancer initiation and progression. Although genomic technologies have been used to gain a better understanding of the impact of gene expression heterogeneity on breast cancer outcome by identifying gene expression signatures associated with clinical outcome, histopathological breast cancer subtypes, and a variety of cancer--related pathways and processes, relatively little is known about the influence of of heterogeneity in the tumor microenvironment on these factors. We show that gene expression in the breast tumor microenvironment is highly heterogeneous, identifying at least six different classes of tumor stroma with distinct expression patterns and distinct biological processes. Two of these classes recapitulate the processes identified in the stroma--derived prognostic predictor, while the others are new classes of stroma associated with distinct clinical outcomes. One of these is associated with matrix remodeling and is strongly associated with the basal molecular subtype of breast cancer. The remainder are independent of the previously published molecular subtypes of breast cancer. Additionally, based on independent data from over 800 tumors, the combinations of stroma classes and breast cancer subtypes identify new subgroups of breast tumors that show better discrimination between good and poor outcome individuals than the molecular breast cancer subtypes or the stroma classes alone, suggesting a novel classification scheme for breast cancer . This further demonstrates an important role for the tumor microenvironment in defining breast cancer heterogeneity, with a consequent impact upon clinical outcome.
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Project description:Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.
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Project description:Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and elucidation of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, identifying potential therapeutic targets, and uncovering stromal gene expression signatures that may predict clinical outcome. A key issue to resolve, therefore, is whether the stromal response to tumor growth is largely a generic phenomenon, irrespective of the tumor type, or whether the response reflects tumor-specific properties. To address similarity or distinction of stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to compare the transcriptomes of laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma. Invasive breast and prostate cancer-associated stroma was observed to display distinct transcriptomes, with a limited number of shared genes. Interestingly, both breast and prostate tumor-specific dysregulated stromal genes were observed to cluster breast and prostate cancer patients, respectively, into two distinct groups with statistically different clinical outcomes. By contrast, a gene signature that was common to the reactive stroma of both tumor types did not have survival predictive value. Univariate Cox analysis identified genes whose expression level was most strongly associated with patient survival. Taken together, these observations suggest that the tumor microenvironment displays distinct features according to the tumor type that provides survival-predictive value. 6 samples of stroma surrounding invasive breast primary tumors; 6 matched samples of normal stroma. 6 samples of stroma surrounding invasive prostate primary tumors; 6 matched samples of normal stroma.
2011-03-31 | E-GEOD-26910 | biostudies-arrayexpress
Project description:Triple-negative breast cancer represents approximately 15–20% of all reported breast cancer cases, and is characterized by a shorter survival time and higher mortality rates compared to other breast cancer sub-types. Tumor microenvironment (TME) refers to the internal and external environment of tumor tissue. Increasing evidence indicates that a tumor’s microenvironment is tightly associated with the immunological surveillance and defense during the development of breast cancer. Although oncology studies employing digital dissection methodologies have provided some insight on the biological features of TME, the development of methods to investigate the cellular composition of the tumor microenvironment remain an important research priority. In this study, we extracted whole transcriptome from 30 Triple-negative breast cancer (TNBC) patients and then used bioinformatics approaches to characterize cell type content in tumor tissue compared with para-cancerous tissue. We identified 4 types of enriched immune cells and 6 types of downregulated immune cells in the tumor tissue samples. After comprehensive bioinformatics analyses, we developed an ‘immune infiltration score’ (IIS) to quantitatively model immune cell infiltration in TNBC. To demonstrate the utility of the IIS, we used 2 independent datasets for validation. We found that patients with a higher IIS showing a longer progression-free survival time and significantly better prognosis than those with a lower IIS value. In sum, we explored the immune infiltration landscape in 30 TNBC patients and provided a novel and reliable biomarker IIS to evaluate the progression-free survival and prognosis in the TNBC patients.
2021-10-18 | E-MTAB-10886 | biostudies-arrayexpress
Project description:Solid tumors are composed of cancer cells and host immune cells that are distributed in a non-uniform pattern. Growing evidence shows that intratumoral microbes are associated with immune microenvironments in cancer. However, mechanisms that direct the recruitment of microbes to tumors remain poorly understood. Here, we show that intratumoral infiltration of immune cells and microbes are heterogeneous, and the distribution of microbes within tumors are orchestrated by the spatial heterogeneity of intratumoral lymphoid populations. Analysis of human solid tumors revealed that the spatial distribution of immune cells, particularly CD8+ T cells, is markedly heterogeneous. Compared to T cell-poor (“cold”) tumor nests, T cell-rich (“hot”) tumor nests displayed a significantly higher number of myeloid cells, B cells, and plasma cells. We performed laser capture microdissection (LCM) followed by RNA sequencing to identify unique gene signatures that define tumor epithelium and stroma of cold and hot tumor nests. Cold tumor nests expressed genes that promote tumor proliferation and fibrosis, whereas hot tumor stroma and epithelium showed upregulation of immune-related processes, including responses to bacteria, and receptors that mediate mucosal immune responses to microbes, respectively. Consistent with these findings, we detected elevated levels of microbes within hot tumor nests in human pancreatic and lung cancers as well as in mouse models of pancreatic cancer. Intratumoral T cell infiltration plays a causal role in spatial distribution of bacteria in tumor. Our data implicate intratumoral immune heterogeneity in defining microbial spatial distribution and highlight a potential role for crosstalks between microbes, cancer cells, and the host immune system in shaping constituents of the tumor microenvironment (TME).
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Project description:Immune checkpoint inhibitors (ICIs) have had a profound impact on the treatment of many tumors; however, their effectiveness against triple-negative breast cancers (TNBCs) has been limited. One factor limiting responsiveness of TNBCs to ICIs is a lack of functional tumor i-infiltrating lymphocytes (TILs) in ‘“non-inflamed’” or ‘“cold’” tumor immune microenvironments (TIMEs), albeitalthough by unknown mechanisms. Targeting MUC1-C in a mouse transgenic TNBC tumor model increases cytotoxic tumor -infiltrating CD8 + T cells (CTLs), supporting a role for MUC1-C in immune evasion. The basis for these findings and whether they extend to human TNBCs are not known.
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Project description:Background: IL-33, a cytokine with pleiotropic functions, is elevated in serum of patients with hepatocellular carcinoma (HCC). This study investigated effects of local IL-33 expression in resected HCC on patient survival and on immunological and molecular tumor microenvironment. Methods: Tissue of resected HCCs was stained for H&E, masson trichrome, alpha smooth muscle actin, IL-33, CD8 and IL-13 and analysed by flow cytometry. Besides histomorphologic evaluation, the immunohistochemical stainings were analysed for the respective cell numbers separately for tumor area, infiltrative margin and distant liver stroma. These findings were correlated with clinical data and patient outcome. Further, gene expression of different HCC risk groups was compared using Micro Arrays. Results: In multivariable analysis, infiltration of HCCs by IL-33+ cells (P=0.032) and CD8+ cells (P=0.014) both independently were associated with prolonged patient survival. Flow cytometry demonstrated that cytotoxically active CD8+CD62L-KLRG1+CD107a+ effectory-memory cells are the main producers of IL-33 in these HCC patients. Using infiltration by IL-33+ and CD8+ cells as two separate factors, a HCC immune score (HCCIS) was designed and evaluated that stratified patient survival (P=0.0004). This HCCIS identified high and low risk patients who differ in gene expression profiles (P<0.001). Conclusion: Infiltration of HCCs by IL-33+ and CD8+ cells is independently associated with prolonged patient survival. We suggest that this is due to an induction of highly effective cytotoxically active CD8+CD62L-KLRG1+CD107a+ effector-memory cells producing IL-33. Based on these two independent factors we established a HCC immune score that provides risk stratification for HCC patients and can be used in the clinical setting. To investigate if HCCIS 0 high risk and HCCIS 2 low risk tumors exhibit a distinct molecular environment and gene expression pattern, RNA from fresh tumor tissue was isolated and analyzed by whole genome Microarray 4 patients with low risk tumors (HCCIS 2) were compared to 4 patients with high risk tumors (HCCIS 0).
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Project description:Analysis of B16 tumor microenvironments at gene expression level. The hypothesis tested in the present study was that Tregs orchastrated the immune reponse triggered in presence of tumors Total RNA obtained from tumor microenvironment tissues (at Day 4 and Day 14 after tumor inoculation) compared to control tissues.
2016-09-01 | E-GEOD-73384 | biostudies-arrayexpress