Identification of prognostic and therapeutic value of CC chemokines in Urothelial bladder cancer: evidence from comprehensive bioinformatic analysis

Abstract Background Urothelial bladder cancer (BC) is one of the most prevalent malignancies with high mortality and high recurrence rate. Angiogenesis, tumor growth and metastasis of multiple cancers are partly modulated by CC chemokines. However, we know little about the function of distinct CC chemokines in BC. Methods ONCOMINE, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan–Meier plotter, cBioPortal, GeneMANIA, and TIMER were used for analyzing differential expression, prognostic value, protein–protein interaction, genetic alteration and immune cell infiltration of CC chemokines in BC patients based on bioinformatics. Results The results showed that transcriptional levels of CCL2/3/4/5/14/19/21/23 in BC patients were significantly reduced. A significant relation was observed between the expression of CCL2/11/14/18/19/21/23/24/26 and the pathological stage of BC patients. BC patients with high expression levels of CCL1, CCL2, CCL3, CCL4, CCL5, CCL8, CCL13, CCL15, CCL17, CCL18, CCL19, CCL22, CCL25, CCL27 were associated with a significantly better prognosis. Moreover, we found that differentially expressed CC chemokines are primarily correlated with cytokine activity, chemokines receptor binding, chemotaxis, immune cell migration. Further, there were significant correlations among the expression of CC chemokines and the infiltration of several types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Conclusions This study is an analysis to the potential role of CC chemokines in the therapeutic targets and prognostic biomarkers of BC, which gives a novel insight into the relationship between CC chemokines and BC.

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Immune Profiling Reveals Molecular Classification and Characteristic in Urothelial Bladder Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.596484 ◽

2021 ◽

Vol 9 ◽

Author(s):

Li Yang ◽

Aitian Li ◽

Fengsen Liu ◽

Qitai Zhao ◽

Shaofei Ji ◽

...

Keyword(s):

Bladder Cancer ◽

Tumor Microenvironment ◽

Signaling Pathways ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Tumor Subtype ◽

Urothelial Bladder Cancer ◽

Urothelial Bladder ◽

Immune Profiling

Urothelial bladder cancer (UBC) is the most common malignant tumor of the urinary system. Most patients do not benefit from treatment with immune checkpoint inhibitors, which are closely associated with immune profiling in the context of UBC. Therefore, we aimed to characterize the immune profile of UBC to identify different immune subtypes that may influence therapy choice. We identified four subtypes of UBC based on immune profiling including immune ignorant, cold tumor, immune inactive, and hot tumor. After excluding the cold tumor subtype because of its unique pathology distinct from the other types, a high correlation between patient survival and immune characteristics was observed. Most immune cell types had highly infiltrated the hot tumor subtype compared to other subtypes. Interestingly, although immune cells infiltrated the tumor microenvironment, they exhibited an exhaustion phenotype. CCL4 may be the key molecule functioning in immune cell infiltration in the hot tumor subtype. Moreover, neutrophils may function as an important suppressor in the tumor microenvironment of the immune ignorant and immune inactive subtypes. Furthermore, different tumor-intrinsic signaling pathways were involved in immune cell infiltration and exclusion in these four different subtypes. Immune profiling could serve as a prognostic biomarker for UBC, and has potential to guide treatment decisions in UBC. Targeting tumor-intrinsic signaling pathways may be a promising strategy to treat UBC.

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Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFβ2 mediated pathway

PLoS ONE ◽

10.1371/journal.pone.0200079 ◽

2018 ◽

Vol 13 (7) ◽

pp. e0200079 ◽

Cited By ~ 5

Author(s):

Ciputra Adijaya Hartana ◽

Emma Ahlén Bergman ◽

A. Ali Zirakzadeh ◽

David Krantz ◽

Malin E. Winerdal ◽

...

Keyword(s):

Bladder Cancer ◽

T Cells ◽

Cd8 T Cells ◽

Urothelial Bladder Cancer ◽

Urothelial Bladder ◽

Perforin Expression

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Clinical activity, safety, and biomarkers of MPDL3280A in metastatic urothelial bladder cancer: Additional analysis from phase IA study.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.297 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 297-297 ◽

Cited By ~ 7

Author(s):

Joseph W. Kim ◽

Joaquim Bellmunt ◽

Thomas Powles ◽

Yohann Loriot ◽

Nicholas J. Vogelzang ◽

...

Keyword(s):

Bladder Cancer ◽

Complex Disease ◽

Immune Cell ◽

Marker Gene ◽

Tumor Burden ◽

Clinical Activity ◽

Urothelial Bladder Cancer ◽

Primary Resistance ◽

Urothelial Bladder

297 Background: Metastatic urothelial bladder cancer (UBC) is a mutationally-complex disease in which PD-L1 expression in the tumor microenvironment may inhibit immune-mediated antitumor responses. MPDL3280A is a PD-L1-targeting antibody with an engineered Fc domain that disrupts PD-L1/PD-1 and PD-L1/B7.1 signaling. Methods: MPDL3280A was studied in a phase Ia metastatic UBC expansion cohort. UBC pts received MPDL3280A 15 mg/kg IV q3w for ≤16 cycles. Efficacy-evaluable pts were dosed by January 27, 2014 (≥12 week follow-up) with a data cutoff of April 21, 2014. RECIST v1.1 was used to assess ORR. PD-L1 expression (by immune cell IHC) was centrally evaluated from archival biopsies. In-tumor gene expression and peripheral biomarker analyses were done on pts dosed by Nov 20, 2013, with a cutoff of January 1, 2014. Results: In the UBC cohort, 33 IHC 2/3 pts, 36 IHC 0/1 pts, and 1 PD-L1 pt with unknown IHC were efficacy-evaluable. Median pt age was 65 y (36-89), and 73% were male. Visceral and liver metastases were present in 74% and 33% of pts, respectively. 73% had ≥2 prior therapies, and 91% had prior platinum. The unconfirmed ORR was 52% (95% CI, 34-69; 3 CRs, 14 PRs) in IHC 2/3 pts and 14% (95% CI, 6-28; 5 PRs) in IHC 0/1 pts. The median DOR was not yet reached (0.1+ to 42+ w in IHC 2/3 pts, n=17; 6+ to 19+ w in IHC 0/1 pts, n=5). 19/22 responding pts had ongoing responses. Median PFS was 24 w in IHC 2/3 pts (5 to 50+ w, n=33) and 8 w in IHC 0/1 pts (0.1+ to 30+ w, n=36). Of 74 pts evaluable for safety, all grade treatment-related AEs occurred in 65%, most often fatigue, decreased appetite and nausea. 5% had treatment-related G3-4 AEs. No treatment-related deaths were seen. The median follow-up was 5.4 mos (1+ to 12 mos, n=70). IHC 2/3 tumors had low expression of a baseline myeloid marker gene signature, including IL8 and IL1B, which was associated with MPLD3280A response. Additionally, circulating inflammatory markers (e.g., CRP) and tumor burden markers (e.g., HCG) decreased in responders by cycle 2. Updated data will be presented. Conclusions: MPDL3280A was well tolerated in UBC pts. Rapid and durable responses were seen and correlated with PD-L1 IHC status on immune cells. Biomarkers suggest a potential role for myeloid biology in primary resistance to MPDL3280A. Clinical trial information: NCT01375842.

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