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

Author:

Zhang Min,Bzura Aleksandra,Baitei Essa Y.,Zhou ZisenORCID,Spicer Jake B.ORCID,Poile Charlotte,Rogel Jan,Branson Amy,King Amy,Barber Shaun,Kamata TamihiroORCID,Dzialo JoannaORCID,Harber James,Greystoke AlastairORCID,Nusrat Nada,Faulkner DanielORCID,Sun Qianqian,Nolan Luke,Hahne Jens C.,Scotland Molly,Walter HarrietORCID,Darlison Liz,Morgan Bruno,Bajaj Amrita,Brookes Cassandra,Hollox Edward J.ORCID,Lubawska Dominika,Jama Maymun,Griffiths Gareth,Nakas Apostolos,Kutywayo Kudzayi,Luo Jin-Li,Klampatsa AsteroORCID,Cooper AndreaORCID,Halder Koirobi,Wells-Jordan Peter,Zhou Huiyu,Dudbridge FrankORCID,Thomas Anne,Richards Catherine Jane,Pritchard Catrin,Yang HongjiORCID,Barer Michael,Fennell Dean A.ORCID

Abstract

AbstractMalignant 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.

Funder

Cancer Research UK

Asthma + Lung UK VPDCF17-17 Victor Dahdaleh Foundation

Publisher

Springer Science and Business Media LLC

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