Multi-omics Perspective on the Tumor Microenvironment based on PD-L1 and CD8 T-Cell Infiltration in Urothelial Cancer

Chen, Siteng; Zhang, Ning; Shao, Jianhua; Wang, Tao; Wang, Xiang

doi:10.7150/jca.28494

Cited by 17 publications

(24 citation statements)

References 25 publications

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“…Recently, an association between immune cells, such as CD8 tumor-infiltrating lymphocytes, in the tumor microenvironment and the survival of BCa patients was further confirmed [21,22]. In addition, the molecular characteristics of immune cells were considered by an immune classification based on T cell infiltration, as in the TMIT classification (tumor microenvironment immune type: PD-L1 and CD8) or a classification published by our group with a unique immune evasion phenotype with constitutive overexpression of PD-L1 on tumor cells [23,24]. However, it would be helpful to identify a few or a single protein marker expressed in tumor cells and immune cells that is associated with prognosis in BCa.…”

Section: Introductionmentioning

confidence: 77%

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

Eckstein

Epple

Jung

et al. 2020

Cancers

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Bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide. Although there are several well-established molecular and immunological classifications, markers for tumor cells and immune cells that are associated with prognosis are still needed. The chemokine CC motif ligand 2 (CCL2) could be such a marker. We analyzed the expression of CCL2 by immunohistochemistry (IHC) in 168 muscle invasive BCa samples using a tissue microarray. Application of a single cut-off for the staining status of tumor cells (TCs; positive vs. negative) and immune cells (ICs; ≤6% of ICs vs. >6% of ICs) revealed 57 cases (33.9%) and 70 cases (41.7%) with CCL2-positive TCs or ICs, respectively. IHC results were correlated with clinicopathological and survival data. Positive CCL2 staining in TCs was associated with shorter overall survival (OS), disease-specific survival (DSS), and relapse-free survival (RFS) (p = 0.004, p = 0.036, and p = 0.047; log rank test) and appeared to be an independent prognostic factor for OS (RR = 1.70; p = 0.007; multivariate Cox’s regression analysis). In contrast, positive CCL2 staining in the ICs was associated with longer OS, DSS, and RFS (p = 0.032, p = 0.001, and p = 0.001; log rank test) and appeared to be an independent prognostic factor for DSS (RR = 1.77; p = 0.031; multivariate Cox’s regression analysis). Most interestingly, after separating the patients according to their lymph node status (N0 vs. N1+2), CCL2 staining in the ICs was differentially associated with prognosis. In the N0 group, CCL2 positivity in the ICs was a positive independent prognostic factor for OS (RR = 1.99; p = 0.014), DSS (RR = 3.17; p = 0.002), and RFS (RR = 3.10; p = 0.002), whereas in the N1+2 group, CCL2 positivity was a negative independent factor for OS (RR = 3.44; p = 0.019)) and RFS (RR = 4.47; p = 0.010; all multivariate Cox’s regression analyses). In summary, CCL2 positivity in TCs is a negative prognostic factor for OS, and CCL2 can mark ICs that are differentially associated with prognosis depending on the nodal stage of BCa patients. Therefore, CCL2 staining of TCs and ICs is suggested as a prognostic biomarker for BCa patients.

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Section: Introductionmentioning

confidence: 77%

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

Eckstein

Epple

Jung

et al. 2020

Cancers

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“…Despite significant advances in understanding cancer biology, including the functional role of the TME, the treatment of patients with BC still remains challenging. As migration of immune cells into the tumour site is closely related to clinical results and disease outcome, these cells could be used as drug targets to improve survival of patients with BC [10][11][12]. However, immunophenotyping in cancer could be problematic as the existing experimental methods such as immunochemistry require multiple biomarkers and can miss certain cell populations.…”

Section: Introductionmentioning

confidence: 99%

In silico analysis of the immune microenvironment in bladder cancer

Zhang

Zhuang

et al. 2020

BMC Cancer

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Background: Infiltrating immune and stromal cells are vital components of the bladder cancer (BC) microenvironment, which can significantly affect BC progression and outcome. However, the contribution of each subset of tumour-infiltrating immune cells is unclear. The objective of this study was to perform cell phenotyping and transcriptional profiling of the tumour immune microenvironment and analyse the association of distinct cell subsets and genes with BC prognosis. Methods: Clinical data of 412 patients with BC and 433 transcription files for normal and cancer tissues were downloaded from The Cancer Genome Atlas. The CIBERSORT algorithm was used to determine the relative abundance of 22 immune cell types in each sample and the ESTIMATE algorithm was used to identify differentially expressed genes within the tumour microenvironment of BC, which were subjected to functional enrichment and protein-protein interaction (PPI) analyses. The association of cell subsets and differentially expressed genes with patient survival and clinical parameters was examined by Cox regression analysis and the Kaplan-Meier method. Results: Resting natural killer cells and activated memory CD4 + and CD8 + T cells were associated with favourable patient outcome, whereas resting memory CD4 + T cells were associated with poor outcome. Differential expression analysis revealed 1334 genes influencing both immune and stromal cell scores; of them, 97 were predictive of overall survival in patients with BC. Among the top 10 statistically significant hub genes in the PPI network, CXCL12, FN1, LCK, and CXCR4 were found to be associated with BC prognosis. Conclusion: Tumour-infiltrating immune cells and cancer microenvironment-related genes can affect the outcomes of patients and are likely to be important determinants of both prognosis and response to immunotherapy in BC.

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“…In addition to this, recent genomic and transcriptomic analyses of the TCGA bladder cancer cohort, classified bladder cancer into 4 tumor microenvironment immune types (TMITs) based on the PD-L1 expression and the presence of CD8+ cytotoxic lymphocytes (CTLs). Higher overall mutational burden and co-occurrence of mutations in P53 and RB genes were associated with TMIT I group of tumors that present high expression levels of both CD8A and PD-L1 in addition to IFNγ gene signature, unlike TMIT II–IV [11].…”

Section: Introductionmentioning

confidence: 99%

The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

et al. 2019

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BackgroundBladder cancer (BC) is the most common malignant disease of the urinary tract. Recurrent high grade non muscle invasive BC carries a serious risk for progression and subsequent metastases. The most common preclinical mouse model for bladder cancer relies on administration of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to mice. BBN-induced tumors in mice recapitulate the histology of human BC and were characterized with an overexpression of markers typical for basal-like cancer subtype in addition to a high mutational burden with frequent mutations in Trp53, similar to human muscle invasive BC.MethodsBladder cancer was induced in C57BL/6J male mice by administering the BBN in the drinking water. A thorough histopathological analysis of bladder specimen during and post BBN treatment was performed at 2, 4, 16, 20 and 25 weeks. RNA sequencing and qPCR was performed to assess the levels of expression of immunologically relevant genes at 2 weeks and 20 weeks during and post BBN treatment.ResultsWe characterized the dynamics of the inflammatory response in the BBN-induced BC in mice. The treatment with BBN had gradually induced a robust inflammation in the first 2 weeks of administration, however, the inflammatory response was progressively silenced in the following weeks of the treatment, until the progression of the primary carcinoma. Tumors at 20 weeks were characterized with a marked upregulation of IL18 when compared to premalignant inflammatory response at 2 weeks. In accordance with this, we observed an increase in expression of IFNγ-responsive genes coupled to a pronounced lymphocytic infiltrate during the early stages of malignant transformation in bladder. Similar to human basal-like BC, BBN-induced murine tumors displayed an upregulated expression of immunoinhibitory molecules such as CTLA-4, PD-L1, and IDO1 which can lead to cytotoxic resistance and tumor escape.ConclusionsDespite the recent advances in bladder cancer therapy which include the use of checkpoint inhibitors, the treatment options for patients with locally advanced and metastatic BC remain limited. BBN-induced BC in mice displays an immunological profile which shares similarities with human MIBC thus representing an optimal model for preclinical studies on immunomodulation in management of BC.

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Multi-omics Perspective on the Tumor Microenvironment based on PD-L1 and CD8 T-Cell Infiltration in Urothelial Cancer

Cited by 17 publications

References 25 publications

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

In silico analysis of the immune microenvironment in bladder cancer

The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

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