A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma

Min Zhang, Aleksandra Bzura, Essa Y. Baitei, Zisen Zhou, Jake B. Spicer, Charlotte Poile, Jan Rogel, Amy Branson, Amy King, Shaun Barber, Tamihiro Kamata, Joanna Dzialo, James Harber, Alastair Greystoke, Nada Nusrat, Daniel Faulkner, Qianqian Sun, Luke Nolan, Jens C. Hahne, Molly Scotland, Harriet Walter, Liz Darlison, Bruno Morgan, Amrita Bajaj, Cassandra Brookes, Edward J. Hollox, Dominika Lubawska, Maymun Jama, Gareth Griffiths, Apostolos Nakas, Kudzayi Kutywayo, Jin-Li Luo, Astero Klampatsa, Andrea Cooper, Koirobi Halder, Peter Wells-Jordan, Huiyu Zhou, Frank Dudbridge, Anne Thomas, Catherine Jane Richards, Catrin Pritchard, Hongji Yang, Michael Barer and Dean A. Fennell ()
Additional contact information
Min Zhang: University of Leicester
Aleksandra Bzura: University of Leicester
Essa Y. Baitei: University of Leicester
Zisen Zhou: University of Leicester
Jake B. Spicer: University of Leicester
Charlotte Poile: University of Leicester
Jan Rogel: University of Leicester
Amy Branson: University of Leicester
Amy King: University Hospitals of Leicester NHS Trust
Shaun Barber: University of Leicester
Tamihiro Kamata: University of Leicester
Joanna Dzialo: University of Leicester
James Harber: Harry Perkins Institute of Medical Research and The University of Western Australia Centre for Cancer Research
Alastair Greystoke: Northern Centre for Cancer Care
Nada Nusrat: University of Leicester
Daniel Faulkner: University of Leicester
Qianqian Sun: Novogene Corporation
Luke Nolan: University Hospital Southampton NHS Foundation Trust
Jens C. Hahne: University of Leicester
Molly Scotland: University Hospitals of Leicester NHS Trust
Harriet Walter: University of Leicester
Liz Darlison: Mesothelioma
Bruno Morgan: University Hospitals of Leicester NHS Trust
Amrita Bajaj: University Hospitals of Leicester NHS Trust
Cassandra Brookes: University of Leicester
Edward J. Hollox: University of Leicester
Dominika Lubawska: University of Leicester
Maymun Jama: University of Leicester
Gareth Griffiths: University of Southampton Clinical Trials Unit
Apostolos Nakas: University Hospitals of Leicester NHS Trust
Kudzayi Kutywayo: University Hospitals of Leicester NHS Trust
Jin-Li Luo: University of Leicester
Astero Klampatsa: Institute of Cancer Research
Andrea Cooper: University of Leicester
Koirobi Halder: University of Leicester
Peter Wells-Jordan: University of Leicester
Huiyu Zhou: University of Leicester
Frank Dudbridge: University of Leicester
Anne Thomas: University of Leicester
Catherine Jane Richards: University Hospitals of Leicester NHS Trust
Catrin Pritchard: University of Leicester
Hongji Yang: University of Leicester
Michael Barer: University of Leicester
Dean A. Fennell: University of Leicester

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49842-5

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