Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer

Abstract Background Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). Although classical molecular subtypes effectively reflect TME heterogeneity and characteristics, their clinical application is limited by several issues. Methods In this study, we integrated the Xiangya cohort and multiple external BLCA cohorts to develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system and a corresponding quantitative indicator, the 5mC score. Unsupervised clustering was performed to identify novel 5mC regulator-mediated molecular subtypes. The principal component analysis was applied to calculate the 5mC score. Then, we correlated the 5mC clusters (5mC score) with classical molecular subtypes, immunophenotypes, clinical outcomes, and therapeutic opportunities in BLCA. Finally, we performed pancancer analyses on the 5mC score. Results Two 5mC clusters, including 5mC cluster 1 and cluster 2, were identified. These novel 5mC clusters (5mC score) could accurately predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic opportunities of BLCA. 5mC cluster 1 (high 5mC score) indicated a luminal subtype and noninflamed phenotype, characterized by lower anticancer immunity but better prognosis. Moreover, 5mC cluster 1 (high 5mC score) predicted low sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy, but high sensitivity to antiangiogenic therapy and targeted therapies, such as blocking the β-catenin, FGFR3, and PPAR-γ pathways. Conclusions The novel 5mC regulator-based subtype system reflects many aspects of BLCA biology and provides new insights into precision medicine in BLCA. Furthermore, the 5mC score may be a generalizable predictor of immunotherapy response and prognosis in pancancers.

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PMEPA1 Is a Prognostic Biomarker That Correlates With Cell Malignancy and the Tumor Microenvironment in Bladder Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.705086 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dongxu Qiu ◽

Jian Hu ◽

Jiao Hu ◽

Anze Yu ◽

Belaydi Othmane ◽

...

Keyword(s):

Bladder Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Molecular Subtype ◽

Transmembrane Protein ◽

Treatment Options ◽

Potential Biomarker ◽

Cell Malignancy

Prostate transmembrane protein androgen induced 1 (PMEPA1) has been reported to promote cancer progression, but the potential role of PMEPA1 in bladder cancer (BLCA) remains elusive. We assess the role of PMEPA1 in BLCA, via a publicly available database and in vitro study. PMEPA1 was identified from 107 differentially expressed genes (DEGs) to have prognostic value. GO, KEGG, and GSEA analysis indicated that PMEPA1 was involved in cancer progression and the tumor microenvironment (TME). Then bioinformatical analysis in TCGA, GEO, TIMER, and TISIDB show a positive correlation with the inflammation and infiltration levels of three tumor-infiltrating immune cells (TAMs, CAFs, and MDSCs) and immune/stromal scores in TME. Moreover, in vitro study revealed that PMEPA1 promotes bladder cancer cell malignancy. Immunohistochemistry and survival analysis shed light on PMEPA1 potential to be a novel biomarker in predicting tumor progression and prognosis. At last, we also analyzed the role of PMEPA1 in predicting the molecular subtype and the response to several treatment options in BLCA. We found that PMEPA1 may be a novel potential biomarker to predict the progression, prognosis, and molecular subtype of BLCA.

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The Tumor Microenvironment and Immunotherapy in Prostate and Bladder Cancer

Urologic Clinics of North America ◽

10.1016/j.ucl.2020.10.005 ◽

2020 ◽

Vol 47 (4) ◽

pp. e17-e54

Author(s):

Sujit S. Nair ◽

Rachel Weil ◽

Zachary Dovey ◽

Avery Davis ◽

Ashutosh K. Tewari

Keyword(s):

Bladder Cancer ◽

Tumor Microenvironment

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Integrated clinicopathologic and molecular risk stratification for disease recurrence in muscle-invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.490 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 490-490

Author(s):

Ruben Carmona ◽

Alan Pollack ◽

Zachary L Smith ◽

Jeff M. Michalski ◽

Hiram Alberto Gay ◽

...

Keyword(s):

Bladder Cancer ◽

Risk Stratification ◽

Molecular Subtype ◽

Disease Recurrence ◽

Invasive Bladder Cancer ◽

Training Set ◽

Combined Model ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive ◽

Testing Set

490 Background: Integrating molecular subtypes, gene transcripts associated with disease recurrence (DR), and clinicopathologic features may help risk stratify muscle-invasive bladder cancer (MIBC) patients & guide therapy selection. We hypothesized that combined transcriptomic & clinical data would improve risk stratification for DR (local or distant) after cystectomy +/- adjuvant chemotherapy. Methods: We identified 401 MIBC patients (pT2-4 N0-N3 M0) in The Cancer Genome Atlas with detailed demographic, clinical, pathologic, and treatment-related data. We split the data into training (60%) & testing (40%) sets. We produced RNA gene expression scores for molecular subtype using 48 established, relevant genes (PMID 28988769). In the training set, we performed feature selection by conducting random forest modeling of an additional 108 genes associated with DR. We kept genes of highest importance based on the evaluation of increasing mean-squared error & node purity. We excluded highly correlated genes & used the false discovery rate method for multiple hypotheses testing. We performed univariable analyses on genes of highest importance, molecular subtype, & clinicopathologic variables. Using adjusted multivariable analyses (MVA), we built two models: with & without transcriptomic data. Using the testing set, we compared the final models' performance to predict DR, using receiver operating characteristics & area under the curve (AUC). Results: Median follow-up was 18 months (range 1-168). 104 patients recurred with a 5-yr cumulative incidence of 34.6%[28.6-40.5%]. Using the training set, we identified 6 genes significantly associated with DR (VEGFA, TRMT1, FGFR2B, ERBB2, MMP14, PDGFC). The final MVA showed that the new 6-gene signature (HR 1.61, 95% CI 1.27-2.05, p < 0.001); immune molecular subtype [increased expression of PD-L1, PD-1, IDO1, CXCL11, L1CAM, SAA1] (HR 0.52, 95% CI 0.29-0.94, p = 0.03); smoking status (HR 1.17 per 10 pack-years, 95% CI 1.05-1.29, p = 0.005); and local failure risk factors [≥pT3 with negative margins & ≥10 nodes removed (HR 1.63, 95% CI 1.15-2.32, p = 0.006); ≥pT3 and positive margins OR < 10 nodes removed (HR 3.26, 95%CI 2.43 to 4.09, p = 0.007)], were all significantly associated with DR. This combined model outperformed a stand-alone clinicopathologic model (AUC 0.75 vs. 0.66) in the testing set. The combined model stratified patients based on DR risk into 3 groups with 5-yr cumulative incidences of 19.8%[7.7-31.9%] (low-risk); 34.5%[26.1-42.8%] (intermediate); and 49.8%[37.7-61.9%] (high), Gray’s Test p < 0.0001. Conclusions: To our knowledge, this study is the first to integrate clinicopathologic & transcriptomic information (including molecular subtype) to better stratify MIBC patients by risk of recurrence. This stratification may help guide decision-making for adjuvant treatment. Further validation is warranted.

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A qPCR ‐based method for molecular subtype classification of urinary bladder cancer ‐ stromal gene expressions show higher prognostic values than intrinsic tumor genes

International Journal of Cancer ◽

10.1002/ijc.33809 ◽

2021 ◽

Author(s):

Csilla Olah ◽

Christina Hahnen ◽

Nikolett Nagy ◽

Joanna Musial ◽

Melinda Varadi ◽

...

Keyword(s):

Bladder Cancer ◽

Urinary Bladder ◽

Molecular Subtype ◽

Urinary Bladder Cancer ◽

Gene Expressions ◽

Subtype Classification

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Epigenetic regulation of mammalian Hedgehog signaling to the stroma determines the molecular subtype of bladder cancer

eLife ◽

10.7554/elife.43024 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 5

Author(s):

SungEun Kim ◽

Yubin Kim ◽

JungHo Kong ◽

Eunjee Kim ◽

Jae Hyeok Choi ◽

...

Keyword(s):

Bladder Cancer ◽

Urothelial Carcinoma ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Molecular Mechanisms ◽

Molecular Subtype ◽

Early Stage ◽

Human Bladder Cancer ◽

Human Bladder ◽

Stromal Response

In bladder, loss of mammalian Sonic Hedgehog (Shh) accompanies progression to invasive urothelial carcinoma, but the molecular mechanisms underlying this cancer-initiating event are poorly defined. Here, we show that loss of Shh results from hypermethylation of the CpG shore of the Shh gene, and that inhibition of DNA methylation increases Shh expression to halt the initiation of murine urothelial carcinoma at the early stage of progression. In full-fledged tumors, pharmacologic augmentation of Hedgehog (Hh) pathway activity impedes tumor growth, and this cancer-restraining effect of Hh signaling is mediated by the stromal response to Shh signals, which stimulates subtype conversion of basal to luminal-like urothelial carcinoma. Our findings thus provide a basis to develop subtype-specific strategies for the management of human bladder cancer.

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Accounting for B cell behaviour and sampling bias yields a superior predictor of anti-PD-L1 response in bladder cancer

10.1101/2021.03.04.433370 ◽

2021 ◽

Author(s):

Ilya A Dyugay ◽

Daniil K Lukyanov ◽

Maria A Turchaninova ◽

Andrew R Zaretsky ◽

Oybek A Khalmurzaev ◽

...

Keyword(s):

Bladder Cancer ◽

T Cell ◽

B Cells ◽

B Cell ◽

Molecular Subtype ◽

Specific Antigen ◽

Therapy Response ◽

Prognostic Indicator ◽

Molecular Signature ◽

Cell Functions

Tumor-infiltrating B cells and intratumorally-produced immunoglobulins (IG) play important roles in the tumor microenvironment and response to immunotherapy. IgG antibodies produced by intratumoral B cells may drive antibody-dependent cellular cytotoxicity (ADCC) and enhance antigen presentation by dendritic cells. Furthermore, B cells are efficient antigen-specific antigen presenters that can essentially modulate the behaviour of helper T cells. Here we investigated the role of intratumoral IG isotype and clonality in bladder cancer. Our results show that the IgG1/IgA ratio offers a strong and independent prognostic indicator for the Basal squamous molecular subtype and for the whole ImVigor210 cohort in anti-PD-L1 immunotherapy. Our findings also indicate that effector B cell functions, rather than clonally-produced antibodies, are involved in the antitumor response. High IgG1/IgA ratio was associated with relative abundance of cytotoxic genes and prominence of the IL-21/IL-21R axis suggesting importance of T cell/B cell interaction. We integrated the B, NK, and T cell components, employing immFocus-like normalization to account for the stochastic nature of tumor tissue sampling. Using a random forest model with nested cross-validation, we developed a tumor RNA-Seq-based predictor of anti-PD-L1 therapy response in muscle-invasive urothelial carcinoma. The resulting PRIMUS (PRedIctive MolecUlar Signature) predictor achieves superior sensitivity compared to PD-L1 expression scores or existing gene signatures, allowing for reliable identification of responders even within the desert patient subcohort analyzed as a hold out set.

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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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