Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients

Study information

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study design

time series / longitudinal observational

Citation

PMID PubMed identifier for scientific articles.

39481388

DOI Digital object identifier for electronic documents.

10.1016/j.chom.2024.10.006

URI

Authors

Macandog ADG, Catozzi C, Capone M, Nabinejad A, Nanaware PP, Liu S, Vinjamuri S, Stunnenberg JA, Galiè S, Jodice MG, Montani F, Armanini F, Cassano E, Madonna G, Mallardo D, Mazzi B, Pece S, Tagliamonte M, Vanella V, Barberis M, Ferrucci PF, Blank CU, Bouvier M, Andrews MC, Xu X, Santambrogio L, Segata N, Buonaguro L, Cocorocchio E, Ascierto PA, Manzo T, Nezi L

Journal

Cell host & microbe

Year

2024

Keywords:

antigen mimicry, gut microbiome, immunotherapy, longitudinal, melanoma

Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach-reactive CD8+ T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides.

Experiment 1

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Curated date: 2024/11/19

Curator: Joiejoie

Revision editor(s): Joiejoie

Subjects

Location of subjects

Italy

Host species Species from which microbiome was sampled. Contact us to have more species added.

Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology

Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology

Melanoma malignant melanoma,melanoma,melanoma (disease),melanoma, malignant,Naevocarcinoma,Melanoma

Group 0 name Corresponds to the control (unexposed) group for case-control studies

non-complete responders (nCR)

Group 1 name Corresponds to the case (exposed) group for case-control studies

complete responders (CR)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group

This group represents the Complete Responders (CR) to anti-PD-1 therapy in melanoma patients for 2-6 months (early therapy) .

Group 0 sample size Number of subjects in the control (unexposed) group

9

Group 1 sample size Number of subjects in the case (exposed) group

14

Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)

30 days

Lab analysis

Sequencing type

16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene

V3-V4

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance

Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).

log transformation

Statistical test

MaAsLin2

Significance threshold p-value or FDR threshold used for differential abundance testing (if any)

0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?

Yes

LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool

2.0

Signature 1

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Curated date: 2024/11/19

Curator: Joiejoie

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Source: Figure S2D

Description: This figure highlights the microbial taxa dynamics associated with treatment response, emphasizing the potential role of specific gut microbiota in influencing clinical outcomes during anti-PD-1 therapy.

Abundance in Group 1: increased abundance in complete responders (CR)

NCBI	Quality Control	Links
Candidatus Metalachnospira gallinarum
Clostridia
Candidatus Roslinia caecaviumCandidatus Roslinia caecavium
Candidatus Metaruminococcus gallistercorisCandidatus Metaruminococcus gallistercoris
Candidatus Gallimonas caecicolaCandidatus Gallimonas caecicola
Candidatus Heteroscilispira lomaniiCandidatus Heteroscilispira lomanii
Veillonellaceae_SGB5809_groupVeillonellaceae_SGB5809_group
Bacteroides nordii
Bifidobacterium pseudolongum
Bifidobacterium pullorum

Revision editor(s): Joiejoie

Signature 2

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Curated date: 2024/11/20

Curator: Joiejoie

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Source: Figure S2D

Description: This figure highlights the microbial taxa dynamics associated with treatment response, emphasizing the potential role of specific gut microbiota in influencing clinical outcomes during anti-PD-1 therapy.

Abundance in Group 1: decreased abundance in complete responders (CR)

NCBI	Quality Control	Links
Clostridia_unclassified_SGB6369Clostridia_unclassified_SGB6369
Clostridia_unclassified_SGB14951Clostridia_unclassified_SGB14951
Clostridia_unclassified_SGB6293Clostridia_unclassified_SGB6293
Anaerostipes__caccaeAnaerostipes__caccae
Clostridiales_bacterium_S5_A14aClostridiales_bacterium_S5_A14a
p_Firmicutes_SGB47515p_Firmicutes_SGB47515
f_Bacteroidales_unclassified_SGB2173f_Bacteroidales_unclassified_SGB2173
Clostridiales_bacterium_BX7Clostridiales_bacterium_BX7
Carnobacterium_maltaromaticumCarnobacterium_maltaromaticum
Evtepia_gabavorousEvtepia_gabavorous
Eubacterium_maltosivoransEubacterium_maltosivorans
Clostridium_SGB6179Clostridium_SGB6179
Aggregatibacter_sp_oral_taxon_458Aggregatibacter_sp_oral_taxon_458
Candidatus_Cryptoclostridium_obscurumCandidatus_Cryptoclostridium_obscurum

Revision editor(s): Joiejoie

Experiment 2

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Curated date: 2024/11/22

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Differences from previous experiment shown

Subjects

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group

This group represents the Complete Responders (CR) to anti-PD-1 therapy in melanoma patients for 7-13 months (late therapy).

Lab analysis

Sequencing type

WMS

16S variable region One or more hypervariable region(s) of the bacterial 16S gene

Not specified

Statistical Analysis

LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool

0

Signature 1

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Needs review

Curated date: 2024/11/27

Curator: Joiejoie

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Source: S1B

Description: Highlights the longitudinal profiling of gut microbiota changes associated with treatment response. It compares the stable taxa identified in complete responders (CR) and non-complete responders (nCR) at various time points throughout the therapy.

Abundance in Group 1: increased abundance in complete responders (CR)

NCBI	Quality Control	Links
Alistipes_sp_An66Alistipes_sp_An66
Bacteroides_sp_Marseille_P3684Bacteroides_sp_Marseille_P3684

Revision editor(s): Joiejoie

Signature 2

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Mark reviewed

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Curated date: 2024/11/27

Curator: Joiejoie

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Source: Figure S1B

Description: Highlights the longitudinal profiling of gut microbiota changes associated with treatment response. It compares the stable taxa identified in complete responders (CR) and non-complete responders (nCR) at various time points throughout the therapy.

Abundance in Group 1: decreased abundance in complete responders (CR)

NCBI	Quality Control	Links
GGB1350_SGB1808GGB1350_SGB1808
GGB12796_SGB19893GGB12796_SGB19893
Alistipes_sp_AF17_16Alistipes_sp_AF17_16
Clostridiaceae_bacterium_NSJ_31Clostridiaceae_bacterium_NSJ_31
Blautia_schinkiiBlautia_schinkii

Revision editor(s): Joiejoie