Gut microbiome for predicting immune checkpoint blockade-associated adverse events.

Publisher: BioMed Central Country of Publication: England NLM ID: 101475844 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-994X (Electronic) Linking ISSN: 1756994X NLM ISO Abbreviation: Genome Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central

Neoplasms*/drug therapy ; Gastrointestinal Microbiome* ; Antineoplastic Agents, Immunological*/therapeutic use ; Drug-Related Side Effects and Adverse Reactions* ; Immune System Diseases* ; Lung Neoplasms*/drug therapy; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; RNA, Ribosomal, 16S/genetics ; Vitamin K 2/therapeutic use ; Immunotherapy/adverse effects ; Programmed Cell Death 1 Receptor ; Retrospective Studies

Background: The impact of the gut microbiome on the initiation and intensity of immune-related adverse events (irAEs) prompted by immune checkpoint inhibitors (ICIs) is widely acknowledged. Nevertheless, there is inconsistency in the gut microbial associations with irAEs reported across various studies.
Methods: We performed a comprehensive analysis leveraging a dataset that included published microbiome data (n = 317) and in-house generated data from 16S rRNA and shotgun metagenome samples of irAEs (n = 115). We utilized a machine learning-based approach, specifically the Random Forest (RF) algorithm, to construct a microbiome-based classifier capable of distinguishing between non-irAEs and irAEs. Additionally, we conducted a comprehensive analysis, integrating transcriptome and metagenome profiling, to explore potential underlying mechanisms.
Results: We identified specific microbial species capable of distinguishing between patients experiencing irAEs and non-irAEs. The RF classifier, developed using 14 microbial features, demonstrated robust discriminatory power between non-irAEs and irAEs (AUC = 0.88). Moreover, the predictive score from our classifier exhibited significant discriminative capability for identifying non-irAEs in two independent cohorts. Our functional analysis revealed that the altered microbiome in non-irAEs was characterized by an increased menaquinone biosynthesis, accompanied by elevated expression of rate-limiting enzymes menH and menC. Targeted metabolomics analysis further highlighted a notably higher abundance of menaquinone in the serum of patients who did not develop irAEs compared to the irAEs group.
Conclusions: Our study underscores the potential of microbial biomarkers for predicting the onset of irAEs and highlights menaquinone, a metabolite derived from the microbiome community, as a possible selective therapeutic agent for modulating the occurrence of irAEs.
(© 2024. The Author(s).)

Bioinformatics. 2020 Jul 1;36(13):4099-4101. (PMID: 32339223)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Nat Med. 2022 Mar;28(3):545-556. (PMID: 35228752)
Oncologist. 2018 Jul;23(7):849-851. (PMID: 29666298)
Nat Rev Drug Discov. 2022 Jul;21(7):495-508. (PMID: 34316029)
Cell. 2020 Aug 6;182(3):655-671.e22. (PMID: 32603654)
Proc Natl Acad Sci U S A. 2019 Nov 5;116(45):22699-22709. (PMID: 31636208)
Ann Transl Med. 2021 Jun;9(12):1034. (PMID: 34277834)
Science. 2021 Feb 5;371(6529):602-609. (PMID: 33303685)
Am J Surg Pathol. 2017 May;41(5):643-654. (PMID: 28296676)
Eur J Cancer. 2009 Jan;45(2):228-47. (PMID: 19097774)
Cancer Cell. 2015 Apr 13;27(4):450-61. (PMID: 25858804)
Ann Oncol. 2017 Nov 01;28(11):2860-2865. (PMID: 29045560)
Nat Med. 2021 Aug;27(8):1432-1441. (PMID: 34239137)
PLoS One. 2019 May 21;14(5):e0217276. (PMID: 31112568)
Cancers (Basel). 2021 May 21;13(11):. (PMID: 34063829)
Cell. 2021 Mar 18;184(6):1575-1588. (PMID: 33675691)
Allergol Int. 2022 Apr;71(2):169-178. (PMID: 35101349)
Nat Med. 2019 Apr;25(4):679-689. (PMID: 30936547)
Nat Rev Clin Oncol. 2022 Apr;19(4):254-267. (PMID: 35082367)
J Clin Oncol. 2015 Oct 1;33(28):3193-8. (PMID: 26282644)
Trends Cancer. 2021 Jul;7(7):583-593. (PMID: 33741313)
J Clin Oncol. 2017 Dec 1;35(34):3815-3822. (PMID: 28915085)
Nat Methods. 2016 Jul;13(7):581-3. (PMID: 27214047)
Therap Adv Gastroenterol. 2019 Sep 16;12:1756284819870911. (PMID: 31555343)
Proc Natl Acad Sci U S A. 2018 Jan 2;115(1):157-161. (PMID: 29255057)
Clin Cancer Res. 2021 May 1;27(9):2571-2583. (PMID: 33593881)
Cancer Cell. 2021 Oct 11;39(10):1314-1316. (PMID: 34637746)
N Engl J Med. 2012 Jun 28;366(26):2443-54. (PMID: 22658127)
BMJ. 2018 Mar 14;360:k793. (PMID: 29540345)
Immunol Rev. 2023 Sep;318(1):167-178. (PMID: 37578634)
Nature. 2010 Mar 4;464(7285):59-65. (PMID: 20203603)
Cell. 2021 Oct 14;184(21):5309-5337. (PMID: 34624224)
Nat Biotechnol. 2020 Jun;38(6):685-688. (PMID: 32483366)
Int J Mol Sci. 2019 May 10;20(9):. (PMID: 31083359)
J Immunother Cancer. 2019 Nov 15;7(1):306. (PMID: 31730012)
Cancer Immunol Immunother. 2019 Apr;68(4):553-561. (PMID: 30666357)
Nat Med. 2021 Mar;27(3):504-514. (PMID: 33603241)
Cancer Discov. 2021 Mar;11(3):614-625. (PMID: 33257470)
Trends Immunol. 2021 Apr;42(4):293-311. (PMID: 33714688)
Science. 2013 Dec 20;342(6165):1432-3. (PMID: 24357284)
Nat Commun. 2016 Feb 02;7:10391. (PMID: 26837003)
Anal Chim Acta. 2007 May 22;591(2):148-54. (PMID: 17481401)
J Dairy Sci. 2013 Mar;96(3):1335-46. (PMID: 23332840)
Semin Cancer Biol. 2020 Oct;65:164-175. (PMID: 31911189)
Nat Metab. 2022 Jul;4(7):867-882. (PMID: 35788761)
Biotechnol Adv. 2020 Mar - Apr;39:107453. (PMID: 31629792)
Allergy. 2022 Aug 2;:. (PMID: 35917214)
BMC Cancer. 2021 Jul 13;21(1):808. (PMID: 34256732)
Front Immunol. 2020 Oct 06;11:2023. (PMID: 33123120)
Thorac Cancer. 2022 Oct;13(19):2681-2691. (PMID: 36043345)
Genome Biol. 2022 Oct 3;23(1):208. (PMID: 36192803)
Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27509-27515. (PMID: 33077598)
Nat Rev Immunol. 2020 Nov;20(11):651-668. (PMID: 32433532)
Ann Oncol. 2017 Oct 01;28(10):2377-2385. (PMID: 28945858)
Nat Commun. 2022 Nov 10;13(1):6818. (PMID: 36357393)
Nat Methods. 2018 Nov;15(11):962-968. (PMID: 30377376)
Cell Host Microbe. 2013 Aug 14;14(2):207-15. (PMID: 23954159)
Ann Oncol. 2017 Jun 01;28(6):1368-1379. (PMID: 28368458)
Nucleic Acids Res. 2009 Jan;37(Database issue):D141-5. (PMID: 19004872)
Genome Med. 2024 Jan 19;16(1):16. (PMID: 38243343)
Nat Med. 2019 Jun;25(6):968-976. (PMID: 31171880)
Nat Microbiol. 2021 Mar;6(3):277-288. (PMID: 33432149)
Cancer Immunol Res. 2020 Oct;8(10):1243-1250. (PMID: 32847937)
Nat Commun. 2021 May 24;12(1):3063. (PMID: 34031391)
Nat Biotechnol. 2019 Aug;37(8):852-857. (PMID: 31341288)
Lancet Oncol. 2018 Dec;19(12):1579-1589. (PMID: 30442497)
J Exp Med. 2023 Mar 6;220(3):. (PMID: 36622383)
Nat Rev Clin Oncol. 2022 Apr;19(4):269-280. (PMID: 35039679)

82073115 National Natural Science Foundation of China; 82002487 National Natural Science Foundation of China; 81973346 National Natural Science Foundation of China; 2022YFE0125300 Key Technologies Research and Development Program; 2019M660142 China Postdoctoral Science Foundation

Keywords: Gut microbiome; Immune checkpoint inhibitors; Immune-related adverse events; Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1)

0 (Immune Checkpoint Inhibitors)
0 (Antineoplastic Agents, Immunological)
0 (RNA, Ribosomal, 16S)
11032-49-8 (Vitamin K 2)
0 (Programmed Cell Death 1 Receptor)

Date Created: 20240119 Date Completed: 20240122 Latest Revision: 20240706

20250114

PMC10799412

10.1186/s13073-024-01285-9

38243343