Epithelial-mesenchymal transition (EMT), T cell infiltration, and outcomes with nivolumab (nivo) in urothelial cancer (UC)

Galsky, Matthew D.; Wang, L.; Saci, Abdel; Szabó, Pavol; Gong, Yixuan; Zhu, Jun

doi:10.1093/annonc/mdx371.005

Cited by 12 publications

(11 citation statements)

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“…Objective responses were observed in 25.5% and 11.3% of patients with high and low CD8 + T cell infiltration, respectively. The median OS was 11.3 and 5.72 months [ 67 ]. Similarly, in the IMvigor 210, a phase II trial evaluating the efficacy of atezolizumab in mUC, CD8 + T cell infiltration was higher in patients who responded to atezolizumab ( p = 0.0265) [ 68 ].…”

Section: The Predictive Value Of Tumor-infiltrating Immune Cells Fmentioning

confidence: 99%

Prognostic and Predictive Value of Tumor-Infiltrating Immune Cells in Urothelial Cancer of the Bladder

Wilpe

Gerretsen

Heijden

et al. 2020

Cancers

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The prognosis and responsiveness to chemotherapy and checkpoint inhibitors differs substantially among patients with bladder cancer (BC). There is an unmet need for biomarkers that can accurately predict prognosis and treatment outcome. Here, we describe the available literature on the prognostic and predictive value of tumor-infiltrating immune cells in BC. Current evidence indicates that a high density of tumor-infiltrating CD8+ T cells is a favorable prognostic factor, whereas PD-L1 expression and tumor-associated macrophages are unfavorable prognostic features. While PD-L1 expression appears unsuccessful as a biomarker for the response to checkpoint inhibitors, there are some indications that high CD8+ T cell infiltration, low transforming growth factor-beta signaling and low densities of myeloid-derived suppressor cells are associated with response. Future studies should focus on combinations of biomarkers to accurately predict survival and response to treatment.

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Section: The Predictive Value Of Tumor-infiltrating Immune Cells Fmentioning

confidence: 99%

Prognostic and Predictive Value of Tumor-Infiltrating Immune Cells in Urothelial Cancer of the Bladder

Wilpe

Gerretsen

Heijden

et al. 2020

Cancers

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Section: Epithelial-mesenchymal Transition (Emt)mentioning

confidence: 99%

“…One study suggests that EMT presence, determined based on a 200-gene signature expression from The Molecular Signatures Database (MSigDB), may be a potential mechanism of tumor immune evasion during nivolumab treatment of urothelial cancers with high CD8 + T cell infiltration, which are normally immunologically responsive to tumor cells [30]. EMT [30]. EMT has historically been associated with suboptimal response to chemotherapy, progression of disease and development of metastases [53,54].…”

Section: Epithelial-mesenchymal Transition (Emt)mentioning

confidence: 99%

“…In a study of 18 patients treated with pembrolizumab, durvalumab or atezolizumab, CD8 + T cell infiltration assessed by IHC significantly correlated with cancer-specific survival (CSS) ( p = 0.013) [ 29 ]. Of the 212 patients from a phase 2 trial of nivolumab in mBC (CheckMate-275), 106 patient samples were analyzed for CD8 + T cells in the tumor by IHC, and which showed that high CD8 expression is associated with longer PFS ( p = 0.0003) and OS ( p = 0.01) [ 30 ].…”

Section: Cd8 + T Cell Infiltrationmentioning

confidence: 99%

“…In this context, EMT has been associated with more aggressive tumor types [ 53, 54 ]. One study suggests that EMT presence, determined based on a 200-gene signature expression from The Molecular Signatures Database (MSigDB), may be a potential mechanism of tumor immune evasion during nivolumab treatment of urothelial cancers with high CD8 + T cell infiltration, which are normally immunologically responsive to tumor cells [ 30 ]. EMT, as a marker on its own, at high levels is associated with worse ORR (EMT high 13.2% vs EMT low 23.6%), PFS (EMT high 1.91 [ 1.81– 2.46 ] vs EMT low 2.10 [ 1.87– 3.65 ]) and OS (EMT high 6.57 [ 4.96-NR ] vs EMT low (8.74 [ 6.05-NR) 30 ].…”

Section: Cd8 + T Cell Infiltrationmentioning

confidence: 99%

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Molecular Biomarkers of Response to PD-1/ PD-L1 Immune Checkpoint Blockade in Advanced Bladder Cancer1

Jong

et al. 2019

BLC

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Background: The activity of PD-1/PD-L1 inhibitors in the treatment of advanced bladder cancer (BC) is promising for many patients. However, a subset of patients do not benefit from treatment, thus leading to an effort to better identify predictive molecular biomarkers of response. Objective: To conduct a systematic review of the literature on predictive molecular biomarkers associated with response to PD-1 and PD-L1 inhibitors in advanced bladder cancer, defined as locally-advanced, unresectable, or metastatic (mBC) disease. Methods: A search of the literature was performed using Embase (1947-January 2019), Medline (1946-January 2019), and EBM Reviews for Cochrane Central Register of Controlled Trials (as of December 2018). Studies examining the association of molecular biomarkers with clinical outcome in BC treated with PD-1 or PD-L1 monotherapy were included. Outcomes of interest were overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), duration of response, and objective response rate (ORR). Results: Using the study search criteria, 899 unique abstract citations were found, of which 834 did not meet the eligibility criteria. Full text of the remaining 65 citations were screened, and 50 studies excluded, including 18 review articles. Eight additional studies from the bibliography of the review papers were included, making a total of 23 studies. Five PD-1 / PD-L1 antibodies have been tested in BC immunohistochemistry (IHC). These studies used different expression scoring criteria and generally had poor ability to discriminate likelihood for response. Overall, the data suggests CD8 + T cell infiltration is necessary to mediate an antitumor immune response, but other immune cell populations, such as neutrophils may suppress T cell-mediated immunity and efficacy of PD-1/PD-L1 blockade. An IFN␥ signature is a promising predictor, but there needs to be consensus on the optimal gene panel composition, and prospective validation. Tumor mutation burden (TMB) is a promising predictor in six studies reporting on 1200 patients, but there is not a consensus on the optimal definition of "high TMB". Detection of T cell receptor (TCR) clonal expansion has only been conducted in small studies and so its predictive value remains inconclusive. Epithelial-mesenchymal transformation (EMT) and transforming growth factor ␤ (TGF␤) are associated with poor prognosis and possibly intrinsic resistance to PD-1/PD-L1 checkpoint blockade, but more work needs to be done to build upon and confirm the initial findings.

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Intratumoral T cell depletion following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer is associated with poor clinical outcome

Wilpe

Sultan

Gorris

et al. 2022

Cancer Immunol Immunother

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Background Whereas neoadjuvant cisplatin-based chemotherapy (NAC) followed by a radical cystectomy remains the standard treatment for patients with muscle-invasive bladder cancer (MIBC), increasing evidence suggests that checkpoint inhibitors, either alone or in combination with chemotherapy, are effective in the (neo)adjuvant setting. The major aim of this study was to improve our understanding of the immune-modulating effects of NAC in MIBC. Methods Tumor tissue of 81 patients was used, including 60 patients treated with NAC and 21 patients undergoing upfront cystectomy. Multiplex immunohistochemistry was performed to assess CD3+, CD3+CD8+, CD3+CD8−FoxP3−, CD3+FoxP3+, and CD20+ cells. Patients were classified into a favorable or unfavorable outcome group based on the development of a recurrence within a year. Results The density of intratumoral CD3+ T cells decreased following NAC in patients with a recurrence at one year, while it remained stable in patients without a recurrence (median fold change 0.6 [95CI 0.3; 1.0] versus 1.0 [95CI 0.6; 2.2]). This decrease was mainly attributable to a decrease in CD3+CD8−FoxP3− and CD3+FoxP3+ T cells and was not observed in patients with an early recurrence after upfront cystectomy. Additionally, in cystectomy tissue of patients treated with NAC, median CD3+ and CD3+CD8+ T cell densities were significantly lower in patients with versus patients without a recurrence (CD3: 261. cells/mm2 [95CI 22.4; 467.2]; CD8: 189.6 cells/mm2 [95CI 2.0;462.0]). Conclusion T cell density decreases following NAC in MIBC patients with poor clinical outcome. Further research is needed to investigate whether this decrease in T cell density affects the efficacy of subsequent checkpoint inhibitors. Précis The major aim of this study was to improve our understanding of the immune-modulating effects of NAC in patients with MIBC. We reveal a decline in intratumoral CD3+ T cell density following NAC in patients with an early recurrence.

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Epithelial-mesenchymal transition (EMT), T cell infiltration, and outcomes with nivolumab (nivo) in urothelial cancer (UC)

Cited by 12 publications

References 0 publications

Prognostic and Predictive Value of Tumor-Infiltrating Immune Cells in Urothelial Cancer of the Bladder

Prognostic and Predictive Value of Tumor-Infiltrating Immune Cells in Urothelial Cancer of the Bladder

Molecular Biomarkers of Response to PD-1/ PD-L1 Immune Checkpoint Blockade in Advanced Bladder Cancer1

Intratumoral T cell depletion following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer is associated with poor clinical outcome

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