A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma
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<sup>+</sup> 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<sup>+</sup> T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68<sup>+</sup> 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.
Authors
- J. Spicer (ORCID: https://orcid.org/0000-0003-2842-7412)
- Joanna Działo (ORCID: https://orcid.org/0000-0001-6083-7687)
- Dean A. Fennell (ORCID: https://orcid.org/0000-0001-7373-1312)
- Michael R. Barer (ORCID: https://orcid.org/0000-0002-0377-3100)
- Bruno Morgan
- Alastair Greystoke (ORCID: https://orcid.org/0000-0001-9168-0387)
- Kudzayi Kutywayo (ORCID: https://orcid.org/0000-0002-0847-8282)
- James Harber (ORCID: https://orcid.org/0000-0001-6451-9598)
- Amy Branson
- Frank Dudbridge (ORCID: https://orcid.org/0000-0002-8817-8908)
- Harriet S. Walter (ORCID: https://orcid.org/0000-0003-2618-711X)
- Jinli Luo (ORCID: https://orcid.org/0000-0002-9241-5283)
- Shaun Barber (ORCID: https://orcid.org/0000-0002-8073-2687)
- Jens C. Hahne (ORCID: https://orcid.org/0000-0002-0069-0692)
- Maymun Jama
- Apostolos Nakas (ORCID: https://orcid.org/0000-0001-6993-1514)
- Astero Klampatsa (ORCID: https://orcid.org/0000-0003-0572-502X)
- Amrita Bajaj (ORCID: https://orcid.org/0000-0002-9251-2753)
- Cassandra Brookes (ORCID: https://orcid.org/0000-0002-0084-0400)
- Charlotte Poile
- Edward J. Hollox (ORCID: https://orcid.org/0000-0002-0115-2298)
- Essa Y. Baitei
- Tamihiro Kamata (ORCID: https://orcid.org/0000-0002-2032-9300)
- Anne Thomas (ORCID: https://orcid.org/0000-0003-1998-3134)
- Peter Wells-Jordan
- Huiyu Zhou (ORCID: https://orcid.org/0000-0003-1634-9840)
- Molly Scotland
- D.N. Faulkner (ORCID: https://orcid.org/0000-0003-3438-7330)
- Zisen Zhou (ORCID: https://orcid.org/0000-0001-6122-5586)
- Aleksandra Bzura (ORCID: https://orcid.org/0000-0001-5836-4905)
- Nada Nusrat
- Jan Rogel
- Gareth Griffiths (ORCID: https://orcid.org/0000-0002-9579-8021)
- Catrin Pritchard (ORCID: https://orcid.org/0000-0003-1859-4487)
- Liz Darlison (ORCID: https://orcid.org/0000-0003-0157-1860)
- Min Zhang (ORCID: https://orcid.org/0009-0007-4363-8492)
- Hongji Yang (ORCID: https://orcid.org/0000-0001-6561-3631)
- Qianqian Sun (ORCID: https://orcid.org/0000-0002-1244-4405)
- Dominika Lubawska
- Andrea M. Cooper (ORCID: https://orcid.org/0000-0001-6050-3863)
- Koirobi Halder
- Amy King
- C. J. Richards
- Luke Nolan
Institutions
- Institute of Cancer Research (GB)
- University of Leicester (GB)
- The University of Western Australia (AU)
- Harry Perkins Institute of Medical Research (AU)
- King Faisal Specialist Hospital & Research Centre (SA)
- Cancer Research UK (GB)
- University Hospitals of Leicester NHS Trust (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- Northern Health and Social Care Trust (GB)
- National Institute for Health and Care Research (GB)
- Novogene Bioinformatics Institute (CN)
- NIHR Leicester Biomedical Research Centre (GB)
- University of Southampton (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1038/s41467-024-49842-5
- Citations
- 23
- Primary Topic
- Occupational and environmental lung diseases
- Type
- article
- Field-Weighted Citation Impact
- 9.64
Funders
- University Hospitals of Leicester NHS Trust
- Cancer Research UK
- National Institute for Health and Care Research
- British Lung Foundation
- Asthma and Lung UK
- University of Leicester
- Medical Research Council
- NIHR Leicester Biomedical Research Centre