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

• Published in: Nature communications Vol. 15; no. 1; pp. 7187 - 14
• Main Authors: Zhang, Min, Bzura, Aleksandra, Baitei, Essa Y., Zhou, Zisen, Spicer, Jake B., Poile, Charlotte, Rogel, Jan, Branson, Amy, King, Amy, Barber, Shaun, Kamata, Tamihiro, Dzialo, Joanna, Harber, James, Greystoke, Alastair, Nusrat, Nada, Faulkner, Daniel, Sun, Qianqian, Nolan, Luke, Hahne, Jens C., Scotland, Molly, Walter, Harriet, Darlison, Liz, Morgan, Bruno, Bajaj, Amrita, Brookes, Cassandra, Hollox, Edward J., Lubawska, Dominika, Jama, Maymun, Griffiths, Gareth, Nakas, Apostolos, Kutywayo, Kudzayi, Luo, Jin-Li, Klampatsa, Astero, Cooper, Andrea, Halder, Koirobi, Wells-Jordan, Peter, Zhou, Huiyu, Dudbridge, Frank, Thomas, Anne, Richards, Catherine Jane, Pritchard, Catrin, Yang, Hongji, Barer, Michael, Fennell, Dean A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 14/34; 38/39; 38/91; 45/23; 631/67/1059/2325; 631/67/1641; Aged; Aneuploidy; Antibodies, Monoclonal, Humanized - therapeutic use; Asbestos; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Bevacizumab; Bevacizumab - pharmacology; Bevacizumab - therapeutic use; CD8 antigen; Clinical trials; Correlation; Disease control; Female; Gastrointestinal Microbiome - drug effects; Health services; Homologous recombination; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Infiltration; Intestinal microflora; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - microbiology; Lung Neoplasms - pathology; Lymphocytes; Lymphocytes T; Male; Medical prognosis; Mesothelioma; Mesothelioma - drug therapy; Mesothelioma - immunology; Mesothelioma - microbiology; Mesothelioma - pathology; Mesothelioma, Malignant - drug therapy; Metastases; Microbiomes; Microbiota; Microorganisms; Middle Aged; Monocytes; multidisciplinary; Patients; PD-L1 protein; Peritoneum; Resistance factors; Science; Science (multidisciplinary); Treatment Outcome; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors; Underpotential deposition; Uniparental disomy; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49842-5

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. Although immune checkpoint blockade is a standard treatment for patients with malignant mesothelioma, only a minority of patients exhibit radiological response. In a phase II clinical trial (MIST4) investigating the efficacy, safety and molecular correlates of response following treatment with atezolizumab and bevacizumab, the authors demonstrate that the gut microbiota may modulate responsiveness to treatment.