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Updated: Jun 24, 2026
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma
Min Zhang1,2, Aleksandra Bzura1, Essa Y Baitei1,3
1National Institute for Health Research Biomedical Research Centre & Cancer Research UK Experimental Cancer Medicine Centre, University of Leicester, Leicester, UK.
Abstract:
Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.
Insights
This study found that gut bacteria composition influences treatment response in malignant mesothelioma patients receiving atezolizumab and bevacizumab. Modifying the gut microbiome may improve immunotherapy effectiveness for this rare cancer.
Area of Science:
- Oncology
- Immunology
- Microbiome Research
Background:
- Malignant mesothelioma, a rare cancer linked to asbestos exposure, has limited treatment options and poor prognosis.
- Immune checkpoint blockade (ICB) offers survival benefits, but response predictors are unclear.
Purpose of the Study:
- To evaluate atezolizumab and bevacizumab (AtzBev) efficacy in relapsed mesothelioma via a phase II trial (MiST4).
- To identify tumor-intrinsic and extrinsic factors, including gut microbiome, associated with AtzBev treatment response.
Main Methods:
- Multi-center phase II clinical trial (MiST4) assessing AtzBev in relapsed mesothelioma.
- Tumor tissue and gut microbiome sequencing.
- Tumor spatial immunophenotyping.
Main Results:
- The trial met its primary endpoint with 50% 12-week disease control; AtzBev was tolerable.
- Tumor aneuploidy (UPD), HRD, EMT, and CD68+ monocytes were intrinsic resistance factors.
- Gut microbial log-ratio correlated positively with radiological response and CD8+ T cell infiltration, inversely with resistance factors.
Conclusions:
- A model suggests intrinsic and extrinsic mesothelioma factors modulate the tumor microenvironment, impacting AtzBev sensitivity.
- Gut microbiota represent a potentially modifiable target to enhance immunotherapy outcomes in mesothelioma.
