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Updated: Jan 15, 2026
Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
The hypoxic ECM and neutrophils in MIBC immunotherapy resistance
Fraser Child1, Sapna Lunj2, Julie Gough3
1Division of Cancer Sciences, University of Manchester, Manchester, UK. fraser.child@manchester.ac.uk.
Abstract:
Immune-checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD1) and programmed cell death 1 ligand 1 (PDL1) have improved survival for patients with different types of solid tumour. However, clinical response in patients with muscle-invasive bladder cancer (MIBC) is limited, with only 20-30% demonstrating a sustained response. An improved understanding of ICI mechanisms and robust biomarkers will increase efficacy and enable patient stratification in MIBC. Hypoxia (low oxygen tension) and neutrophil infiltration are prevalent in MIBC and are associated with immunotherapy resistance. Hypoxia-associated extracellular matrix (ECM) remodelling can induce pro-tumour or anti-tumour neutrophil polarization through biomechanical and biochemical signalling. Hypoxia-associated ECM mechanisms alter neutrophil recruitment, polarization, activation and affect T cell-centric immunotherapies. However, the specific mechanisms by which hypoxia, ECM and neutrophils confer immunotherapy resistance in MIBC are not yet fully understood. ICI resistance could be overcome by targeting specific ECM remodelling-related and neutrophil-related pathways to elicit durable and efficacious responses in 70-80% of patients with MIBC who are currently non-responsive to ICIs.
Insights
Immune-checkpoint inhibitors show limited response in muscle-invasive bladder cancer. Targeting hypoxia, extracellular matrix, and neutrophils may improve efficacy for non-responders.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Immune-checkpoint inhibitors (ICIs) targeting PD1/PDL1 improve survival in solid tumors.
- Clinical response to ICIs in muscle-invasive bladder cancer (MIBC) is limited (20-30%).
- Hypoxia and neutrophil infiltration are common in MIBC and linked to immunotherapy resistance.
Purpose of the Study:
- To understand mechanisms of ICI resistance in MIBC.
- To identify biomarkers for patient stratification.
- To explore targeting hypoxia, ECM, and neutrophils to overcome ICI resistance.
Main Methods:
- Investigating hypoxia-associated extracellular matrix (ECM) remodeling.
- Analyzing neutrophil recruitment, polarization, and activation under hypoxic conditions.
- Examining the impact of ECM and neutrophils on T cell-mediated immunotherapy.
Main Results:
- Hypoxia-associated ECM remodeling influences neutrophil polarization and function.
- These mechanisms alter immune cell behavior, potentially conferring ICI resistance.
- Specific pathways involving ECM and neutrophils are implicated in immunotherapy resistance.
Conclusions:
- Understanding hypoxia, ECM, and neutrophil interactions is crucial for MIBC immunotherapy.
- Targeting these pathways could enhance ICI efficacy in non-responsive MIBC patients.
- Aims to improve durable responses in 70-80% of non-responders to ICIs.
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