ArticleClinical cancer research : an official journal of the American Association for Cancer Research2021
Myeloid Cell-associated Resistance to PD-1/PD-L1 Blockade in Urothelial Cancer Revealed Through Bulk and Single-cell RNA Sequencing.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 84 citations in OpenAlex.
- Adjuvant nivolumab in muscle-invasive urothelial carcinoma: exploratory biomarker analysis of the randomized phase 3 CheckMate 274 trial.Nature medicine · 2025Trial
- Immune Phenotype in Urothelial Carcinoma: From Tumor Biology to Therapeutic Stratification.Cancers · 2026Review
- Multiomic profiling links L1 retrotransposition to genomic instability and ecDNA in bladder cancer.Nature communications · 2026Article
- A Tumor-Promoting Inflammatory SPP1+ Macrophage-IL6-CRP Axis Drives Immune Dysfunction in Bladder Cancer.Cancer discovery · 2026Article
- Review
- Integrative analysis of myeloid cell signatures identifies a prognostic risk model and potential mechanisms in bladder cancer.Biology direct · 2026Article
- Single-cell sequencing: accurate disease detection.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Article
- From immune exclusion to exhaustion: tumor microenvironment drives therapy response.Frontiers in immunology · 2026Review
- Artificial Intelligence-Enabled Multi-Omics for Predicting Immune Checkpoint Inhibitor Response and Resistance.Journal of multidisciplinary healthcare · 2026Review
- Toward a better pan-tumor predictive signature for unleashing precision immuno-oncology.Journal for immunotherapy of cancer · 2025Review
- Cerium oxide-embedded gold nanoparticles loaded with astragaloside IV for bladder cancer therapy.Scientific reports · 2025Article
- HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.bioRxiv : the preprint server for biology · 2025Article
- Progress in understanding the regulatory mechanisms of immune checkpoint proteins PD-1 and PD-L1 expression.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Review
- BAP1-mediated ubiquitination inhibition and CAS6/AXL signaling activation in bladder cancer progression.Cytotechnology · 2025Article
- Immunomodulation and Immunotherapy for Patients with Prostate Cancer: An Up-to-Date Review.Biomedicines · 2025Review
- COSMIC-021 Phase Ib Study of Cabozantinib Plus Atezolizumab: Results from the Locally Advanced or Metastatic Urothelial Carcinoma Cohorts.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2025Article
- Construction of M2 macrophage-related gene signature for predicting prognosis and revealing different immunotherapy response in bladder cancer patients.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Article
- Blood TCTP as a potential biomarker associated with immunosuppressive features and poor clinical outcomes in metastatic gastric cancer.Journal for immunotherapy of cancer · 2025Article
- Resistance mechanisms to immune checkpoint inhibitors: updated insights.Molecular cancer · 2025Review
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Authors and funding
21 authors at 6 institutions in 2 countries.
Funding
Abstract
purposeTo define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer. EXPERIMENTAL
designWe pursued an unbiased approach using bulk RNA sequencing data from two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures.
resultsWe identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (M
conclusionsThe balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood.
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