Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer

Lisa Derosa ^1,2,3,4, Bertrand Routy ^5,6, Andrew Maltez Thomas ^7,8

¹Gustave Roussy Cancer Campus, Villejuif, France.
²Cancer Medicine Department, Gustave Roussy, Villejuif, France.
³Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée, Ligue Nationale contre le Cancer, Villejuif, France.
⁴Université Paris-Saclay, Ile-de-France, France.
⁵Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Hematology-Oncology Division, Montréal, Quebec, Canada.
⁶Centre de Recherche du CHUM (CRCHUM), Montréal, Quebec, Canada.
⁷Department CIBIO, University of Trento, Trento, Italy.
⁸European Institute of Oncology (IEO) IRCCS, Milan, Italy.
⁹Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
¹⁰Thoracic Oncology Department-CIC1425/CLIP2 Paris-Nord, Hospital Bichat-Claude Bernard, AP-HP, Université Paris-Diderot, Paris, France.
¹¹Pneumology Department, Foch Hospital, Suresnes, France.
¹²Department of Pneumology, Toulouse University Hospital, Toulouse, France.
¹³Pneumology Department, Centre Hospitalier Toulon Sainte-Musse, Toulon, France.
¹⁴Department of Thoracic Oncology, Centre Hospitalier Universitaire, Grenoble, France.
¹⁵UPR 4466, Paris Descartes University, Sorbonne Paris Cité, Paris, France.
¹⁶Department of Medical Oncology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁷Immunomodulatory Therapies Multidisciplinary Study Group (CERTIM), Paris, France.
¹⁸Department of Pulmonary and Thoracic Oncology, University of Lille, University Hospital (CHU), Lille, France.
¹⁹Pulmonary Department, European Hospital, Marseille, France.
²⁰Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France.
²¹Centre de Recherche INSERM LNC-UMR1231, Dijon, France.
²²Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France.
²³Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges-François Leclerc Cancer Center, UNICANCER, Dijon, France.
²⁴EverImmune, Gustave Roussy Cancer Campus, Villejuif, France.
²⁵Centre de Recherche des Cordeliers, INSERM U1138, Equipe labellisée-Ligue contre le cancer, Université de Paris, Institut Universitaire de France, Paris, France.
²⁶Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
²⁷Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
²⁸Université Paris-Saclay, INRAE, MGP, Jouy en Josas, France.
²⁹Centre Hospitalier de Sherbrooke, Sherbrooke, Quebec, Canada.
³⁰INSERM U1018, Oncostat, Villejuif, France.
³¹Department of Radiation Oncology, Gustave Roussy, Villejuif, France.
³²INSERM U1030, Radiothérapie Moléculaire et Innovation Thérapeutique, Villejuif, France.
³³Service des Maladies Respiratoires, Centre Hospitalier d'Aix-en-Provence, Aix-en-Provence, France.
³⁴Gustave Roussy Cancer Campus, Villejuif, France. laurence.zitvogel@gustaveroussy.fr.
³⁵Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée, Ligue Nationale contre le Cancer, Villejuif, France. laurence.zitvogel@gustaveroussy.fr.
³⁶Université Paris-Saclay, Ile-de-France, France. laurence.zitvogel@gustaveroussy.fr.
³⁷Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS) 1428, Villejuif, France. laurence.zitvogel@gustaveroussy.fr.

⁰Gustave Roussy Cancer Campus, Villejuif, France.

Nature Medicine +

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February 4, 2022

View abstract on PubMed

Summary

Fecal Akkermansia muciniphila (Akk) shows promise as a biomarker for immune checkpoint inhibitor (ICI) response in non-small-cell lung cancer (NSCLC). Higher Akk levels correlate with better outcomes, independent of other factors, aiding patient stratification.

Area Of Science

Oncology
Microbiome Research
Immunotherapy

Background

Biomarkers for immune checkpoint inhibitor (ICI) response in non-small-cell lung cancer (NSCLC) are crucial, beyond PD-L1 expression.
Previous research indicated a link between fecal Akkermansia muciniphila (Akk) and clinical benefit from ICIs in NSCLC and kidney cancer patients.

Purpose Of The Study

To prospectively validate the predictive value of fecal Akk in a large cohort of advanced NSCLC patients treated with ICIs.
To investigate the association of Akk abundance with objective response rates and overall survival.

Main Methods

Shotgun metagenomics-based microbiome profiling was conducted on fecal samples from 338 advanced NSCLC patients receiving first- or second-line ICIs.
Multivariate analyses were performed to assess the association of baseline fecal Akk with clinical outcomes, adjusting for covariates like PD-L1 expression, antibiotic use, and performance status.

Main Results

Elevated baseline fecal Akk levels were significantly associated with increased objective response rates and improved overall survival.
Akk abundance was independent of PD-L1 expression, prior antibiotic use, and performance status.
Antibiotic use, observed in 20% of patients, correlated with a relative dominance of Akk (>4.8%) and Clostridium, which were associated with resistance to ICI.

Conclusions

Fecal Akkermansia muciniphila abundance is a potential predictive biomarker for ICI response in NSCLC.
Further studies are warranted to refine patient stratification using Akk as a biomarker.
The interplay between Akk, other gut microbes, and the tumor microenvironment warrants deeper investigation.