Dataset Information

Inhibition of BCL9 Modulates the Cellular Landscape of Tumor-Associated Macrophages in the Tumor Immune Microenvironment of Colorectal Cancer.

ABSTRACT: Tumor-associated macrophages (TAMs) are an indispensable part of the tumor microenvironment (TME), and they likely play a negative rather than positive role in cancer treatment. However, the cellular landscape and transcriptional profile regulation of TAMs in the case of tumor gene inactivation or chemical interference remains unclear. The B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is a critical transcription co-factor of β-catenin. Suppression of Bcl9 inhibits tumor growth in mouse models of colorectal cancer (CRC). Here, we studied the TAMs of CRC by single-cell sequencing. Bcl9 depletion caused macrophage polarization inhibition from M0 to M2 and changed the CRC TME, which further interferes with the inflammation of M0 and M1. The transcription factor regulating these processes may be related to the Wnt signaling pathway from multiple levels. Furthermore, we also found that the cells delineated from monocyte to NK-like non-functioning cells were significantly different in the BCL9-deprived population. Combining these data, we proposed a TAM-to-NK score to evaluate the dynamic balance in TME of monocyte/TAM cells and NK-like non-functioning cells in The Cancer Genome Atlas (TCGA) clinical samples to verify the clinical significance. We demonstrated that the cell type balance and transcription differences of TAMs regulated by BCL9-driven Wnt signaling affected immune surveillance and inflammation of cancer, ultimately affecting patients' prognosis. We thereby highlighted the potential of targeting Wnt signaling pathway through cancer immunotherapy.

SUBMITTER: Wei Z

PROVIDER: S-EPMC8461101 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Understanding the intricate dynamics between adoptively transferred immune cells and the brain tumor immune microenvironment (TIME) is crucial for the development of effective T cell-based immunotherapies. In this study, we investigated the influence of the TIME and chimeric antigen receptor (CAR) design on the anti-glioma activity of B7-H3-specific CAR T-cells. Using an immunocompetent glioma model, we evaluated a panel of seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory, and activation domains. We then investigated changes in the TIME following CAR T-cell therapy using high-dimensional flow cytometry and single-cell RNA sequencing. Our results show that five out of six B7-H3 CARs with single costimulatory domains demonstrated robust functionality in vitro. However, these CARs had significantly varied levels of antitumor activity in vivo. To enhance therapeutic effectiveness and persistence, we incorporated 41BB and CD28 costimulation through transgenic expression of 41BBL on CD28-based CAR T-cells. This CAR design was associated with significantly improved anti-glioma efficacy in vitro but did not result in similar improvements in vivo. Analysis of the TIME revealed that CAR T-cell therapy influenced the composition of the TIME, with the recruitment and activation of distinct macrophage and endogenous T-cell subsets crucial for successful antitumor responses. Indeed, complete brain macrophage depletion using a CSF1R inhibitor abrogated CAR T-cell antitumor activity. In sum, our study highlights the critical role of CAR design and its modulation of the TIME in mediating the efficacy of adoptive immunotherapy for high-grade glioma.SignificanceCAR T-cell immunotherapies hold great potential for treating brain cancers; however, they are hindered by a challenging immune environment that dampens their effectiveness. In this study, we show that the CAR design influences the makeup of the immune environment in brain tumors, underscoring the need to target specific immune components to improve CAR T-cell performance, and highlighting the significance of using models with functional immune systems to optimize this therapy.

Project description:HIGHLIGHTS Preliminary results of this work were presented at the 2016 Academic Surgical Congress, Jacksonville (FL), February 2-4 2016 (Original title: Selective Smo-Inhibition Interferes With Cellular Energetic Metabolism In Colorectal Cancer)This study was funded by "Sapienza-University of Rome" (Funds for young researchers) and "AIRC" (Italian Association for Cancer Research)Hedgehog inhibitor was kindly provided by Genentech, Inc.®. Colon Cancer (CC) is the fourth most frequently diagnosed tumor and the second leading cause of death in the USA. Abnormalities of Hedgehog pathway have been demonstrated in several types of human cancers, however the role of Hedgehog (Hh) in CC remain controversial. In this study, we analyzed the association between increased mRNA expression of GLI1 and GLI2, two Hh target genes, and CC survival and recurrence by gene expression microarray from a cohort of 382 CC patients. We found that patients with increased expression of GLI1 showed a statistically significant reduction in survival. In order to demonstrate a causal role of Hh pathway activation in the pathogenesis of CC, we treated HCT 116, SW480 and SW620 CC cells lines with GDC-0449, a pharmacological inhibitor of Smoothened (SMO). Treatment with GDC-0449 markedly reduced expression of Hh target genes GLI1, PTCH1, HIP1, MUC5AC, thus indicating that this pathway is constitutively active in CC cell lines. Moreover, GDC-0449 partially reduced cell proliferation, which was associated with upregulation of p21 and downregulation of CycD1. Finally, treatment with the same drug reduced migration and three-dimensional invasion, which were associated with downregulation of Snail1, the EMT master gene, and with induction of the epithelial markers Cytokeratin-18 and E-cadherin. These results were confirmed by SMO genetic silencing. Notably, treatment with 5E1, a Sonic Hedgehog-specific mAb, markedly reduced the expression of Hedgehog target genes, as well as inhibited cell proliferation and mediated reversion toward an epithelial phenotype. This suggests the existence of a Hedgehog autocrine signaling loop affecting cell plasticity and fostering cell proliferation and migration/invasion in CC cell lines. These discoveries encourage future investigations to better characterize the role of Hedgehog in cellular plasticity and invasion during the different steps of CC pathogenesis.

Project description:Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.

Dataset Information

Inhibition of BCL9 Modulates the Cellular Landscape of Tumor-Associated Macrophages in the Tumor Immune Microenvironment of Colorectal Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets