Molecular predictors of response to PD-1/PD-L1 inhibition in urothelial cancer

Stühler, Viktoria; Maas, Moritz; Bochem, Jonas; Costa, Inês Anselmo da; Todenhöfer, Tilman; Stenzl, Arnulf; Bedke, Jens

doi:10.1007/s00345-018-2538-6

Cited by 23 publications

(20 citation statements)

References 65 publications

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“…The study we report here follows the analysis of a cohort of advanced stage MIBC. In this setting, understanding the molecular underpinnings of a sample is critical to better predicting how they will respond to therapy(10), especially ICIs (12,13). To better characterize the spatial arrangement of key molecular characteristics such as tumor-intrinsic subtype, TIL exclusion and composition, and tumor-stroma interaction we leveraged multiple traditional bulk and spatial platforms in conjunction highly multiplexed profiling by GeoMx within FFPE tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Historically, protein assessments of the TME have been limited to PDL1 and CD8 single plex IHC staining, which is primarily driven by the observation that in urothelial carcinoma and other cancers, outcomes related to ICI treatment appear particularly favorable in patients with high PD-L1 expression (7,13,14,17,18). But these assays for PD-L1 have been developed for individual therapies, using varying antibody clones, staining protocols, scoring algorithms and cut-offs, which makes standardization across multiple studies difficult (19,20).…”

Section: Introductionmentioning

confidence: 99%

“…Multiple studies have identified distinct RNA expression subtypes within MIBC termed "luminal" and "basal-like" (8), each of which has unique gene expression patterns which have important implications for disease management with conventional chemotherapy (9)(10)(11) and immunotherapies (12). Response to immune checkpoint inhibitors in urothelial bladder cancer has been associated with several potential biomarkers including tumor mutation burden, tumor molecular subtype and PD-L1 expression on CD8+ tumor infiltrating lymphocytes (TILs) and other immune cells (7,(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

“…Comprehensive interrogation of the interaction between these two compartments has proved challenging thus far because most of the foundational work in MIBC has relied on commonly available assays such as single-plex immunohistochemistry (IHC) assays or bulk RNA expression and mutation profiling. With limited availability of tumor tissues during clinical trials, highly multiplexed and quantitative platforms compatible with small formalin-fixed paraffin-embedded (FFPE) tissues are necessary to deliver a comprehensive understanding of the tumor-immune landscape.Historically, protein assessments of the TME have been limited to PDL1 and CD8 single plex IHC staining, which is primarily driven by the observation that in urothelial carcinoma and other cancers, outcomes related to ICI treatment appear particularly favorable in patients with high PD-L1 expression (7,13,14,17,18). But these assays for PD-L1 have been developed for individual therapies, using varying antibody clones, staining protocols, scoring algorithms and cut-offs, which makes standardization across multiple studies difficult (19,20).…”

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confidence: 99%

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Defining the microenvironment landscape of bladder cancer using highly multiplexed spatial genomic and proteomic analysis

Reeves

Zhang²,

Norgaard

et al. 2019

Preprint

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One Sentence Summary:A new method for capturing tumor-immune signaling in FFPE tissues explores how the PPARG signaling axis is associated with immune cell exclusion in bladder cancer. Abstract:Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. PD-1 pathway targeting immunotherapies have been approved to treat advanced bladder cancer, but most patients exhibit primary resistance, suggesting that immune evasion mechanisms exist. The PPARγ pathway has been identified as a potential therapeutic target in MIBC that is associated with reduced CD8+ T-cell infiltration and increased resistance to immunotherapies. We comprehensively profiled the tumor microenvironment (TME) in formalin-fixed, paraffin-embedded (FFPE) tissues from a cohort of PPARγ high (n=13) and PPRARγ low (n=12) MIBC, integrating bulk gene expression, targeted mutation sequencing, immunohistochemistry and multiplex spatial profiling of RNA and protein expression on the GeoMx™ Digital Spatial Profiling (DSP) platform. Molecular subtyping was consistent between traditional methods and GeoMx profiling, and, in this cohort, we observed little evidence of spatial heterogeneity in tumor subtyping. The previously characterized T-cell exclusion phenotype of PPARγ high MIBC was recapitulated on the GeoMx platform and was further extended to show that this is a general phenomenon across immune cell types, supporting potential combination of PPARγ inhibition with ICIs. Furthermore, we found that while immune cells were excluded from PPARγ high tumors, the stromal compartment from these tumors was not significantly different than those PPARγ low tumors. By preserving spatial relationships during the GeoMx analysis, we also identify a novel association between lower immune cell expression in the tumors and higher expression of β-catenin in the stroma, and differential expression of other WNT pathway members associated with PPARγ activity.Patients with the luminal I subtype rarely respond to ICIs(14,15), suggesting the existence of one or more immune escape mechanisms. We previously reported that the PPARγ/RxRa pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC (6,16). In tumors with high PPARγ pathway activity, CD8+ T-cell infiltration appears to be impaired through chemokine suppression, though additional mechanisms may also impact Tcell infiltration. These findings suggest that pharmacological inhibition of PPARγ may induce sensitivity to immunotherapies. To further our understanding of tumor-immune escape mechanisms in MIBC, analysis of both the tumor and the surrounding microenvironment is necessary. Comprehensive interrogation of the interaction between these two compartments has proved challenging thus far because most of the foundational work in MIBC has relied on commonly available assays such as single-plex immunohistochemistry (IHC) assays or bulk RNA expression and mutation profiling. With limited availability of tumor tissues during clinical trials, highly multiplexed and quant...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Defining the microenvironment landscape of bladder cancer using highly multiplexed spatial genomic and proteomic analysis

Reeves

Zhang²,

Norgaard

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…These drugs have revolutionized the management of many cancers in a short period of time, but only a minority of patients benefit, and treatment comes at extraordinary financial cost, as well as with a modest risk of severe toxicity. Stühler et al [6] in this issue of the Journal describe the current state of the art of biomarkers in development to predict response to immunotherapy in bladder cancer. Beyond PD-L1 immunohistochemistry, the two large phase-three trials comparing PD-1/PD-L1 blockade to second-line chemotherapy have not yet reported on correlative biomarkers, which promises to provide the field a big push forward.…”

mentioning

confidence: 99%