Tumor microenvironment and epithelial-mesenchymal transition in bladder cancer: Cytokines in the game?

Martins‐Lima, Cláudia; Chianese, Ugo; Altucci, Lucia; Jerónimo, Carmen; Correia, Margareta P.

doi:10.3389/fmolb.2022.1070383

Cited by 10 publications

(5 citation statements)

References 174 publications

(383 reference statements)

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“…Additionally, intrinsic signaling pathways, which may be influenced by epigenetic changes and genetic mutations, could also lead to increased PD-L1 expression [22]. Furthermore, cytokines might influence the tumor microenvironment, regardless of BCG exposure [6,23]. However, our study clearly indicates that CPS levels show significantly greater changes in patients treated with BCG.…”

Section: Discussionmentioning

confidence: 67%

PD-L1 Expression in High-Risk Non-Muscle-Invasive Bladder Cancer Is Influenced by Intravesical Bacillus Calmette–Guérin (BCG) Therapy

Maas,

Hilsendecker,

Pertoll

et al. 2024

Cancers

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In the expanding landscape of immune checkpoint inhibitors (CPI) in high-risk (HR) non-muscle-invasive bladder cancer (NMIBC), the role of programmed death ligand 1 (PD-L1) as prognostic and predictive is increasingly significant. However, data evaluating its variability and susceptibility to Bacillus Calmette–Guérin (BCG) therapy in HR NMIBC patients is scarce. This retrospective study analyzed 126 HR NMIBC tissue samples from 63 patients (38× BCG-treated, 25× BCG-naïve) at two time points to assess PD-L1 expression using the ‘combined positivity score’ (CPS) with the 22C3 DAKO antibody method and correlated it with clinicopathological parameters. A CPS > 10 defined PD-L1 positivity. The impact of initial PD-L1 status and its change over time on time-to-recurrence, progression-free survival, and overall survival (TTR, PFS, OS) was analyzed using Kaplan–Meier and Cox proportional hazard models. BCG treatment significantly increased PD-L1 expression (5.31 vs. 0.22, p = 0.0423), with PD-L1 positive cases rising post-treatment in the BCG group and remaining unchanged in BCG-naïve patients. Multivariate analysis including T-stage, CIS, grading, tumor size, multifocality, age, and sex revealed a significant correlation between PD-L1 status change to positivity and improved TTR (p = 0.03). Our findings demonstrate a potential modulation of the PD-L1 status by an intravesical BCG therapy. However, its prognostic value appears limited.

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Section: Discussionmentioning

confidence: 67%

PD-L1 Expression in High-Risk Non-Muscle-Invasive Bladder Cancer Is Influenced by Intravesical Bacillus Calmette–Guérin (BCG) Therapy

Maas,

Hilsendecker,

Pertoll

et al. 2024

Cancers

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“…TME comprises various components, including tumor cells, immune cells, inflammatory cells, stem cells, vascular system, fibrous tissue, and extracellular matrix (ECM), and TME has been demonstrated to play a crucial role in the occurrence and progression of BLCA [ 20 ]. Given that CXCL10 may influence BLCA through multiple immune processes, we conducted an analysis of the role of CXCL10 in the TME.…”

Section: Resultsmentioning

confidence: 99%

CXCL10 could be a prognostic and immunological biomarker in bladder cancer

Yin,

Mou,

Zhang

et al. 2024

Discov Onc

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Introduction As proteins that promote immune cell differentiation, chemokines have attracted great interest regarding their role in anti-tumor immune responses within the cancer environment. However, the exact role of CXCL10, a chemokine, in bladder cancer (BLCA) is still not fully elucidated. Method In the present study, we employed bioinformatics approaches to examine the expression pattern, prognostic value, and immune infiltration of CXCL10 in BLCA. Furthermore, we focused on examining the impact of CXCL10 on immune therapy in BLCA. Additionally, we validated the expression of CXCL10 in various BLCA cell lines using PCR techniques. Results We observed an upregulation of CXCL10 in BLCA tissues as well as in different cell lines. Additionally, upregulation of CXCL10 indicates a better prognosis for BLCA patients. ESTIMATE and CIBERSORT algorithms suggest that CXCL10 is closely associated with the immune microenvironment of BLCA. Through multiple immune therapy cohorts, we also identified that CXCL10 has shown promising predictive value for assessing the efficacy of immune therapy in in BLCA. Conclusion Our study indicates that CXCL10 has the potential to serve as a favorable prognostic factor and is strongly associated with immune infiltration in BLCA. Graphical Abstract

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“…Interestingly, we found that virtually all fibroblasts were positive for α-SMA, being classified as myofibroblast-like CAFs (myCAFs) [ 41 ]. MyCAFs play a crucial role in the tumor microenvironment by contributing to the deposition and organization of extracellular matrix components, including collagen and fibronectin, which provide structural support to the growing tumor mass in mouse subcutaneous tumor models [ 42 ]. In this line, the increase in the percentage of myCAFs in the treatment groups could be associated with a remodeling in the tumor’s extracellular matrix by treatments’ actions.…”

Section: Discussionmentioning

confidence: 99%

Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer

Nunes,

Morales,

Rubio

et al. 2024

Cell Death Discov.

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Alterations in the epigenetic machinery in both tumor and immune cells contribute to bladder cancer (BC) development, constituting a promising target as an alternative therapeutic option. Here, we have explored the effects of a novel histone deacetylase (HDAC) inhibitor CM-1758, alone or in combination with immune checkpoint inhibitors (ICI) in BC. We determined the antitumor effects of CM-1758 in various BC cell lines together with the induction of broad transcriptional changes, with focus on the epigenetic regulation of PD-L1. Using an immunocompetent syngeneic mouse model of metastatic BC, we studied the effects of CM-1758 alone or in combination with anti-PD-L1 not only on tumor cells, but also in the tumor microenvironment. In vitro, we found that CM-1758 has cytotoxic and cytostatic effects either by inducing apoptosis or cell cycle arrest in BC cells at low micromolar levels. PD-L1 is epigenetically regulated by histone acetylation marks and is induced after treatment with CM-1758. We also observed that treatment with CM-1758 led to an important delay in tumor growth and a higher CD8 + T cell tumor infiltration. Moreover, anti-PD-L1 alone or in combination with CM-1758 reprogramed macrophage differentiation towards a M1-like polarization state and increased of pro-inflammatory cytokines systemically, yielding potential further antitumor effects. Our results suggest the possibility of combining HDAC inhibitors with immunotherapies for the management of advanced metastatic BC.

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Tumor microenvironment and epithelial-mesenchymal transition in bladder cancer: Cytokines in the game?

Cited by 10 publications

References 174 publications

PD-L1 Expression in High-Risk Non-Muscle-Invasive Bladder Cancer Is Influenced by Intravesical Bacillus Calmette–Guérin (BCG) Therapy

PD-L1 Expression in High-Risk Non-Muscle-Invasive Bladder Cancer Is Influenced by Intravesical Bacillus Calmette–Guérin (BCG) Therapy

CXCL10 could be a prognostic and immunological biomarker in bladder cancer

Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer

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