Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer
Lisa Derosa, Bertrand Routy, Andrew Maltez Thomas, Valerio Iebba, Gerard Zalcman, Sylvie Friard, Julien Mazieres, Clarisse Audigier-Valette, Denis Moro-Sibilot, François Goldwasser, Carolina Alves Costa Silva, Safae Terrisse, Melodie Bonvalet, Arnaud Scherpereel, Hervé Pegliasco, Corentin Richard, François Ghiringhelli, Arielle Elkrief, Antoine Desilets, Felix Blanc-Durand, Fabio Cumbo, Aitor Blanco, Romain Boidot, Sandy Chevrier, Romain Daillère, Guido Kroemer, Laurie Alla, Nicolas Pons, Emmanuelle Le Chatelier, Nathalie Galleron, Hugo Roume, Agathe Dubuisson, Nicole Bouchard, Meriem Messaoudene, Damien Drubay, Eric Deutsch, Fabrice Barlesi, David Planchard, Nicola Segata, Stéphanie Martinez, Laurence Zitvogel, Jean-Charles Soria, Benjamin Besse, Lisa Derosa, Bertrand Routy, Andrew Maltez Thomas, Valerio Iebba, Gerard Zalcman, Sylvie Friard, Julien Mazieres, Clarisse Audigier-Valette, Denis Moro-Sibilot, François Goldwasser, Carolina Alves Costa Silva, Safae Terrisse, Melodie Bonvalet, Arnaud Scherpereel, Hervé Pegliasco, Corentin Richard, François Ghiringhelli, Arielle Elkrief, Antoine Desilets, Felix Blanc-Durand, Fabio Cumbo, Aitor Blanco, Romain Boidot, Sandy Chevrier, Romain Daillère, Guido Kroemer, Laurie Alla, Nicolas Pons, Emmanuelle Le Chatelier, Nathalie Galleron, Hugo Roume, Agathe Dubuisson, Nicole Bouchard, Meriem Messaoudene, Damien Drubay, Eric Deutsch, Fabrice Barlesi, David Planchard, Nicola Segata, Stéphanie Martinez, Laurence Zitvogel, Jean-Charles Soria, Benjamin Besse
Abstract
Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.
Conflict of interest statement
CONFLICTS OF INTEREST
LZ received research contract from Kaleido and Innovate Pharma and Pilege. LD had consulting, and advisory role for BMS, Sanofi and was supported by Philantropia Fondation Gustave Roussy. GZ received a research grant from Fondation Roche, received fees from Roche, MSD, BMS, Astra-Zeneca and is consultant for Da Volterra & Inventiva. ED reports grants and personal fees from Roche Genentech, grants from Boehringer, grants from Astrazeneca, grants and personal fees from Merck Serono, grants from BMS, and grants from MSD. PD had consulting, and advisory role for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung, as well as honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung. PD ran clinical trials as principal or co-investigator for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, and received Travel, Accommodation, Expenses: from AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. FG received honoraria from Amgen,Sanofi, Merk Serono, MSD, BMS, Astra Zeneca, had a consultancy or advisory role for Roche, Enterome and received direct research fundings from Roche, Enterome, Astra Zeneca, Servier and traveling supports from Servier, Amgen, Roche. JCS In the last 2 years consultancy fees from Relay Therapeutics, Gritstone are holds shares from Hookipa, Gritstone, AstraZeneca, Daiichi Sankyo and was a full time employee for AstraZeneca 2017–2019.
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Figures
![Extended Data Fig. 1:](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9330544/bin/nihms-1807276-f0004.jpg)
![Extended Data Fig. 2:](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9330544/bin/nihms-1807276-f0005.jpg)
![Extended Data Fig. 3:](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9330544/bin/nihms-1807276-f0006.jpg)
Extended Data Fig. 4:
Compositional taxonomic differences…
Extended Data Fig. 4:
Compositional taxonomic differences in stools of NSCLC patients segregated according to…
Extended Data Fig. 5:
Interaction between ATB…
Extended Data Fig. 5:
Interaction between ATB and A.muciniphila on survival and microbiome composition. A.…
Extended Data Fig. 6:
Akkp2261 modulated the…
Extended Data Fig. 6:
Akkp2261 modulated the murine microbiome composition, rescuing responsiveness to PD-1 blockade.…
Figure 1.. Stool A. muciniphila (Akk) is…
Figure 1.. Stool A. muciniphila (Akk) is associated with ICI clinical benefit.
Figure 2.. Akk relative abundance represents a…
Figure 2.. Akk relative abundance represents a prognostic marker of ICI.
Figure 3.. Stratification of clinical outcome based…
Figure 3.. Stratification of clinical outcome based on other components of the Akk - associated…
- Too much water drowned the miller: Akkermansia determines immunotherapy responses.Li L, McAllister F. Li L, et al. Cell Rep Med. 2022 May 17;3(5):100642. doi: 10.1016/j.xcrm.2022.100642. Cell Rep Med. 2022. PMID: 35584634 Free PMC article.
- Akk Abundance Alters Survival in Patients with NSCLC on ICIs.[No authors listed] [No authors listed] Cancer Discov. 2022 Apr 1;12(4):OF8. doi: 10.1158/2159-8290.CD-RW2022-027. Cancer Discov. 2022. PMID: 35149527
- PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions.Xia L, Liu Y, Wang Y. Xia L, et al. Oncologist. 2019 Feb;24(Suppl 1):S31-S41. doi: 10.1634/theoncologist.2019-IO-S1-s05. Oncologist. 2019. PMID: 30819829 Free PMC article. Review.
- Efficacy of Immune Checkpoint Inhibitors in KRAS-Mutant Non-Small Cell Lung Cancer (NSCLC).Jeanson A, Tomasini P, Souquet-Bressand M, Brandone N, Boucekine M, Grangeon M, Chaleat S, Khobta N, Milia J, Mhanna L, Greillier L, Biemar J, Nanni I, Ouafik L, Garcia S, Mazières J, Barlesi F, Mascaux C. Jeanson A, et al. J Thorac Oncol. 2019 Jun;14(6):1095-1101. doi: 10.1016/j.jtho.2019.01.011. Epub 2019 Feb 6. J Thorac Oncol. 2019. PMID: 30738221
- HYR-2 plays an anti-lung cancer role by regulating PD-L1 and Akkermansia muciniphila.Teng L, Wang K, Chen W, Wang YS, Bi L. Teng L, et al. Pharmacol Res. 2020 Oct;160:105086. doi: 10.1016/j.phrs.2020.105086. Epub 2020 Jul 17. Pharmacol Res. 2020. PMID: 32687951
- Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC).Hsu PC, Jablons DM, Yang CT, You L. Hsu PC, et al. Int J Mol Sci. 2019 Aug 5;20(15):3821. doi: 10.3390/ijms20153821. Int J Mol Sci. 2019. PMID: 31387256 Free PMC article. Review.
- Gut microbiota in colorectal cancer development and therapy.Wong CC, Yu J. Wong CC, et al. Nat Rev Clin Oncol. 2023 May 11. doi: 10.1038/s41571-023-00766-x. Online ahead of print. Nat Rev Clin Oncol. 2023. PMID: 37169888 Review.
- Dynamic gut microbiota changes in patients with advanced malignancies experiencing secondary resistance to immune checkpoint inhibitors and immune-related adverse events.Zeng Y, Shi Q, Liu X, Tang H, Lu B, Zhou Q, Xu Y, Chen M, Zhao J, Li Y, Qian J, Wang M, Tan B. Zeng Y, et al. Front Oncol. 2023 Apr 11;13:1144534. doi: 10.3389/fonc.2023.1144534. eCollection 2023. Front Oncol. 2023. PMID: 37114123 Free PMC article.
- Prognostic and Predictive Biomarkers in the Era of Immunotherapy for Lung Cancer.Pabst L, Lopes S, Bertrand B, Creusot Q, Kotovskaya M, Pencreach E, Beau-Faller M, Mascaux C. Pabst L, et al. Int J Mol Sci. 2023 Apr 20;24(8):7577. doi: 10.3390/ijms24087577. Int J Mol Sci. 2023. PMID: 37108738 Free PMC article. Review.
- Health and Disease: Akkermansia muciniphila, the Shining Star of the Gut Flora.Xue C, Li G, Gu X, Su Y, Zheng Q, Yuan X, Bao Z, Lu J, Li L. Xue C, et al. Research (Wash D C). 2023;6:0107. doi: 10.34133/research.0107. Epub 2023 Apr 3. Research (Wash D C). 2023. PMID: 37040299 Free PMC article.
- Zengshengping improves lung cancer by regulating the intestinal barrier and intestinal microbiota.Sun E, Meng X, Kang Z, Gu H, Li M, Tan X, Feng L, Jia X. Sun E, et al. Front Pharmacol. 2023 Mar 13;14:1123819. doi: 10.3389/fphar.2023.1123819. eCollection 2023. Front Pharmacol. 2023. PMID: 36992837 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Akkermansia
- B7-H1 Antigen
- Carcinoma, Non-Small-Cell Lung* / drug therapy
- Carcinoma, Non-Small-Cell Lung* / genetics
- Carcinoma, Non-Small-Cell Lung* / metabolism
- Humans
- Lung Neoplasms* / drug therapy
- Lung Neoplasms* / genetics
- Programmed Cell Death 1 Receptor
- Retrospective Studies
- Tumor Microenvironment
- B7-H1 Antigen
- Programmed Cell Death 1 Receptor
- Akkermansia muciniphila
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
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![Extended Data Fig. 4:](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9330544/bin/nihms-1807276-f0007.jpg)
Extended Data Fig. 5:
Interaction between ATB…
Extended Data Fig. 5:
Interaction between ATB and A.muciniphila on survival and microbiome composition. A.…
Extended Data Fig. 6:
Akkp2261 modulated the…
Extended Data Fig. 6:
Akkp2261 modulated the murine microbiome composition, rescuing responsiveness to PD-1 blockade.…
Figure 1.. Stool A. muciniphila (Akk) is…
Figure 1.. Stool A. muciniphila (Akk) is associated with ICI clinical benefit.
Figure 2.. Akk relative abundance represents a…
Figure 2.. Akk relative abundance represents a prognostic marker of ICI.
Figure 3.. Stratification of clinical outcome based…
Figure 3.. Stratification of clinical outcome based on other components of the Akk - associated…
- Too much water drowned the miller: Akkermansia determines immunotherapy responses.Li L, McAllister F. Li L, et al. Cell Rep Med. 2022 May 17;3(5):100642. doi: 10.1016/j.xcrm.2022.100642. Cell Rep Med. 2022. PMID: 35584634 Free PMC article.
- Akk Abundance Alters Survival in Patients with NSCLC on ICIs.[No authors listed] [No authors listed] Cancer Discov. 2022 Apr 1;12(4):OF8. doi: 10.1158/2159-8290.CD-RW2022-027. Cancer Discov. 2022. PMID: 35149527
- PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions.Xia L, Liu Y, Wang Y. Xia L, et al. Oncologist. 2019 Feb;24(Suppl 1):S31-S41. doi: 10.1634/theoncologist.2019-IO-S1-s05. Oncologist. 2019. PMID: 30819829 Free PMC article. Review.
- Efficacy of Immune Checkpoint Inhibitors in KRAS-Mutant Non-Small Cell Lung Cancer (NSCLC).Jeanson A, Tomasini P, Souquet-Bressand M, Brandone N, Boucekine M, Grangeon M, Chaleat S, Khobta N, Milia J, Mhanna L, Greillier L, Biemar J, Nanni I, Ouafik L, Garcia S, Mazières J, Barlesi F, Mascaux C. Jeanson A, et al. J Thorac Oncol. 2019 Jun;14(6):1095-1101. doi: 10.1016/j.jtho.2019.01.011. Epub 2019 Feb 6. J Thorac Oncol. 2019. PMID: 30738221
- HYR-2 plays an anti-lung cancer role by regulating PD-L1 and Akkermansia muciniphila.Teng L, Wang K, Chen W, Wang YS, Bi L. Teng L, et al. Pharmacol Res. 2020 Oct;160:105086. doi: 10.1016/j.phrs.2020.105086. Epub 2020 Jul 17. Pharmacol Res. 2020. PMID: 32687951
- Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC).Hsu PC, Jablons DM, Yang CT, You L. Hsu PC, et al. Int J Mol Sci. 2019 Aug 5;20(15):3821. doi: 10.3390/ijms20153821. Int J Mol Sci. 2019. PMID: 31387256 Free PMC article. Review.
- Gut microbiota in colorectal cancer development and therapy.Wong CC, Yu J. Wong CC, et al. Nat Rev Clin Oncol. 2023 May 11. doi: 10.1038/s41571-023-00766-x. Online ahead of print. Nat Rev Clin Oncol. 2023. PMID: 37169888 Review.
- Dynamic gut microbiota changes in patients with advanced malignancies experiencing secondary resistance to immune checkpoint inhibitors and immune-related adverse events.Zeng Y, Shi Q, Liu X, Tang H, Lu B, Zhou Q, Xu Y, Chen M, Zhao J, Li Y, Qian J, Wang M, Tan B. Zeng Y, et al. Front Oncol. 2023 Apr 11;13:1144534. doi: 10.3389/fonc.2023.1144534. eCollection 2023. Front Oncol. 2023. PMID: 37114123 Free PMC article.
- Prognostic and Predictive Biomarkers in the Era of Immunotherapy for Lung Cancer.Pabst L, Lopes S, Bertrand B, Creusot Q, Kotovskaya M, Pencreach E, Beau-Faller M, Mascaux C. Pabst L, et al. Int J Mol Sci. 2023 Apr 20;24(8):7577. doi: 10.3390/ijms24087577. Int J Mol Sci. 2023. PMID: 37108738 Free PMC article. Review.
- Health and Disease: Akkermansia muciniphila, the Shining Star of the Gut Flora.Xue C, Li G, Gu X, Su Y, Zheng Q, Yuan X, Bao Z, Lu J, Li L. Xue C, et al. Research (Wash D C). 2023;6:0107. doi: 10.34133/research.0107. Epub 2023 Apr 3. Research (Wash D C). 2023. PMID: 37040299 Free PMC article.
- Zengshengping improves lung cancer by regulating the intestinal barrier and intestinal microbiota.Sun E, Meng X, Kang Z, Gu H, Li M, Tan X, Feng L, Jia X. Sun E, et al. Front Pharmacol. 2023 Mar 13;14:1123819. doi: 10.3389/fphar.2023.1123819. eCollection 2023. Front Pharmacol. 2023. PMID: 36992837 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Akkermansia
- B7-H1 Antigen
- Carcinoma, Non-Small-Cell Lung* / drug therapy
- Carcinoma, Non-Small-Cell Lung* / genetics
- Carcinoma, Non-Small-Cell Lung* / metabolism
- Humans
- Lung Neoplasms* / drug therapy
- Lung Neoplasms* / genetics
- Programmed Cell Death 1 Receptor
- Retrospective Studies
- Tumor Microenvironment
- B7-H1 Antigen
- Programmed Cell Death 1 Receptor
- Akkermansia muciniphila
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
![Extended Data Fig. 5:](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9330544/bin/nihms-1807276-f0008.jpg)
Extended Data Fig. 6:
Akkp2261 modulated the…
Extended Data Fig. 6:
Akkp2261 modulated the murine microbiome composition, rescuing responsiveness to PD-1 blockade.…
Figure 1.. Stool A. muciniphila (Akk) is…
Figure 1.. Stool A. muciniphila (Akk) is associated with ICI clinical benefit.
Figure 2.. Akk relative abundance represents a…
Figure 2.. Akk relative abundance represents a prognostic marker of ICI.
Figure 3.. Stratification of clinical outcome based…
Figure 3.. Stratification of clinical outcome based on other components of the Akk - associated…
![Extended Data Fig. 6:](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9330544/bin/nihms-1807276-f0009.jpg)
![Figure 1.. Stool A. muciniphila (Akk) is…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9330544/bin/nihms-1807276-f0001.jpg)
![Figure 2.. Akk relative abundance represents a…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9330544/bin/nihms-1807276-f0002.jpg)
![Figure 3.. Stratification of clinical outcome based…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9330544/bin/nihms-1807276-f0003.jpg)
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