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

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posted on 2024-09-12, 10:20 authored by 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 CooperAndrea Cooper, Koirobi Halder, Peter Wells-Jordan, Huiyu Zhou, Frank Dudbridge, Anne Thomas, Catherine Jane Richards, Catrin Pritchard, Hongji Yang, Michael Barer, Dean A Fennell

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.

History

Author affiliation

College of Life Sciences Genetics, Genome Biology & Cancer Sciences Respiratory Sciences

Version

  • VoR (Version of Record)

Published in

Nat Commun

Volume

15

Issue

1

Pagination

7187

eissn

2041-1723

Copyright date

2024

Available date

2024-09-12

Spatial coverage

England

Language

eng

Deposited by

Dr Jens Hahne

Deposit date

2024-08-23

Data Access Statement

Patient-related data related to this clinical trial shall remain confidential to the sponsor organisation (The University of Leicester) and will not be disclosed except where disclosure might be required in accordance with pharmacovigilance duties of the parties involved. Individual participant data can be made available, after deidentification to investigators who provide written request in accordance with General Data Protection Regulation and following authorisation from the sponsor organisation, starting immediately and ending 3 years after publication. Requests for data and materials will be reviewed by the sponsor and any implications regarding intellectual property or confidentiality considered The WES and RNA-sequencing raw data is available in SRA Run Selector. The data can be publicly accessed upon publication via https://www.ncbi.nlm.nih.gov/bioproject/PRJNA916814, which is hosted by the National Centre for Biotechnology Information, under accession number PRJNA916814. All of the other data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request. Source data are provided with this paper.

Rights Retention Statement

  • Yes