Nature Communications 2024 August 21 [Link]
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, Dean A Fennell
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.
The post A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma appeared first on Mesothelioma Line.
The post A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma appeared first on Mesothelioma Line.
