Dysregulation of tumor microenvironment promotes malignant progression and predicts risk of metastasis in bladder cancer

Low grade gliomas (LGG) account for about two-thirds of all glioma diagnoses in adolescents and young adults (AYA) and malignant progression of these patients leads to dismal outcomes. Recent studies have shown the importance of the dynamic tumor microenvironment in high-grade gliomas (HGG), yet its role is still poorly understood in low-grade glioma malignant progression. Here, we investigated the heterogeneity of the immune microenvironment using a platelet-derived growth factor (PDGF)-driven RCAS (replication-competent ASLV long terminal repeat with a splice acceptor) glioma model that recapitulates the malignant progression of low to high-grade glioma in humans and also provides a model system to characterize immune cell trafficking and evolution. To illuminate changes in the immune cell landscape during tumor progression, we performed single-cell RNA sequencing on immune cells isolated from animals bearing no tumor (NT), LGG and HGG, with a particular focus on the myeloid cell compartment, which is known to mediate glioma immunosuppression. LGGs demonstrated significantly increased infiltrating T cells, CD4 T cells, CD8 T cells, B cells, and natural killer cells in the tumor microenvironment, whereas HGGs significantly abrogated this infiltration. Our study identified two distinct macrophage clusters in the tumor microenvironment; one cluster appeared to be bone marrow-derived while another was defined by overexpression of Trem2, a marker of tumor associated macrophages. Our data demonstrates that these two distinct macrophage clusters show an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG which evolves to an immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG that restricts T cell recruitment and activation. We identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Interestingly, these results were mirrored by our analysis of the TCGA dataset, which demonstrated a statistically significant association between CD74 overexpression and decreased overall survival in AYA patients with grade II gliomas. Targeting immunosuppressive myeloid cells and intra-tumoral macrophages within this therapeutic window may ameliorate mechanisms associated with immunosuppression before and during malignant progression.

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Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer

Science Translational Medicine ◽

10.1126/scitranslmed.abd1346 ◽

2021 ◽

Vol 13 (594) ◽

pp. eabd1346

Author(s):

Christopher S. Garris ◽

Jeffrey L. Wong ◽

Jeffrey V. Ravetch ◽

David A. Knorr

Keyword(s):

Bladder Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Mouse Models ◽

Antitumor Immunity ◽

Bladder Tumor ◽

Immune Surveillance ◽

Disease Recurrence ◽

Bcg Therapy ◽

Agonist Antibody

Intravesical immunotherapy using Bacille Calmette-Guérin (BCG) attenuated bacteria delivered transurethrally to the bladder has been the standard of care for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) for several decades. BCG therapy continues to be limited by high rates of disease recurrence and progression, and patients with BCG-unresponsive disease have few effective salvage therapy options besides radical cystectomy, highlighting a need for new therapies. We report that the immune-stimulatory receptor CD40 is highly expressed on dendritic cells (DCs) within the bladder tumor microenvironment of orthotopic bladder cancer mouse models, recapitulating CD40 expression by DCs found in human disease. We demonstrate that local CD40 agonism in mice with orthotopic bladder cancer through intravesical delivery of anti-CD40 agonist antibodies drives potent antitumor immunity and induces pharmacodynamic effects in the bladder tumor microenvironment, including a reduction in CD8+ T cells with an exhausted phenotype. We further show that type 1 conventional DCs (cDC1) and CD8+ T cells are required for both bladder cancer immune surveillance and anti-CD40 agonist antibody responses. Using orthotopic murine models humanized for CD40 and Fcγ receptors, we demonstrate that intravesical treatment with a fully human, Fc-enhanced anti-CD40 agonist antibody (2141-V11) induces robust antitumor activity in both treatment-naïve and treatment-refractory settings, driving long-term systemic antitumor immunity with no evidence of systemic toxicity. These findings support targeting CD40-expressing DCs in the bladder cancer microenvironment through an intravesical agonistic antibody approach for the treatment of NMIBC.

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Variation in energy metabolism arising from the effect of the tumor microenvironment on cell biological behaviors of bladder cancer cells and endothelial cells

BioFactors ◽

10.1002/biof.1568 ◽

2019 ◽

Vol 46 (1) ◽

pp. 64-75 ◽

Cited By ~ 2

Author(s):

Dan Li ◽

Wei Jiao ◽

Zhijuan Liang ◽

Liping Wang ◽

Yuanbin Chen ◽

...

Keyword(s):

Bladder Cancer ◽

Endothelial Cells ◽

Energy Metabolism ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Bladder Cancer Cells

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CD8+ T Cell Co-Expressed Genes Correlate With Clinical Phenotype and Microenvironments of Urothelial Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.553399 ◽

2020 ◽

Vol 10 ◽

Author(s):

Yutao Wang ◽

Kexin Yan ◽

Jiaxing Lin ◽

Yang Liu ◽

Jianfeng Wang ◽

...

Keyword(s):

Bladder Cancer ◽

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Mhc Class I ◽

Clinical Phenotype ◽

Angiogenesis Inhibitors ◽

Class I ◽

T Cell Infiltration ◽

Tumor Purity

PurposeTo identify immune-related co-expressed genes that promote CD8+ T cell infiltration in bladder cancer, and to explore the interactions among relevant genes in the tumor microenvironment.MethodWe obtained bladder cancer gene matrix and clinical information data from TCGA, GSE32894 and GSE48075. The “estimate” package was used to calculate tumor purity and immune score. The CIBERSORT algorithm was used to assess CD8+ T cell proportions. Weighted gene co-expression network analysis was used to identify the co-expression modules with CD8+ T cell proportions and bladder tumor purity. Subsequently, we performed correlation analysis among angiogenesis factors, angiogenesis inhibitors, immune inflammatory responses, and CD8+ T cell related genes in tumor microenvironment.ResultsA CD8+ T cell related co-expression network was identified. Eight co-expressed genes (PSMB8, PSMB9, PSMB10, PSME2, TAP1, IRF1, FBOX6, ETV7) were identified as CD8+ T cell-related genes that promoted infiltration of CD8+ T cells, and were enriched in the MHC class I tumor antigen presentation process. The proteins level encoded by these genes (PSMB10, PSMB9, PSMB8, TAP1, IRF1, and FBXO6) were lower in the high clinical grade patients, which suggested the clinical phenotype correlation both in mRNA and protein levels. These factors negatively correlated with angiogenesis factors and positively correlated with angiogenesis inhibitors. PD-1 and PD-L1 positively correlated with these genes which suggested PD-1 expression level positively correlated with the biological process composed by these co-expression genes. In the high expression group of these genes, inflammation and immune response were more intense, and the tumor purity was lower, suggesting that these genes were immune protective factors that improved the prognosis in patients with bladder cancer.ConclusionThese co-expressed genes promote high levels of infiltration of CD8+ T cells in an immunoproteasome process involved in MHC class I molecules. The mechanism might provide new pathways for treatment of patients who are insensitive to PD-1 immunotherapy due to low degrees of CD8+ T cell infiltration.

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