The Gut Microbiome Is Associated with Clinical Response to Anti-PD-1/PD-L1 Immunotherapy in Gastrointestinal Cancer

From BugSigDB
Reviewed Marked as Reviewed by Folakunmi on 2024-4-10
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI
Authors
Peng Z, Cheng S, Kou Y, Wang Z, Jin R, Hu H, Zhang X, Gong JF, Li J, Lu M, Wang X, Zhou J, Lu Z, Zhang Q, Tzeng DTW, Bi D, Tan Y, Shen L
Journal
Cancer immunology research
Year
2020
We report on a comprehensive analysis of the gut microbiomes of patients with gastrointestinal (GI) cancer receiving anti-PD-1/PD-L1 treatment. The human gut microbiota has been associated with clinical responses to anti-PD-1/PD-L1 immunotherapy in melanoma, non-small cell lung cancer, and renal cell carcinoma. We aimed to investigate this association in GI cancers. We also identified bacterial taxa with patient stratification potential. We recruited 74 patients with advanced-stage GI cancer receiving anti-PD-1/PD-L1 treatment and collected their fecal samples prior to and during immunotherapy, along with clinical evaluations. Our 16S rRNA taxonomy survey on the fecal samples revealed an elevation of the Prevotella/Bacteroides ratio in patients, with a preferred response to anti-PD-1/PD-L1 treatment, and a particular subgroup of responders harboring a significantly higher abundance of Prevotella, Ruminococcaceae, and Lachnospiraceae The shotgun metagenomes of the same samples showed that patients exhibiting different responses had differential abundance of pathways related to nucleoside and nucleotide biosynthesis, lipid biosynthesis, sugar metabolism, and fermentation to short-chain fatty acids (SCFA). Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti-PD-1/PD-L1 response across different GI cancer types. We further demonstrated that the identified bacterial taxa were predictive of patient stratification in both our cohort and melanoma patients from two previously published studies. Our results thus highlight the impact of gut microbiomes on anti-PD-1/PD-L1 outcomes, at least in a subset of patients with GI cancer, and suggest the potential of the microbiome as a marker for immune-checkpoint blockade responses.See articles by Tomita et al., p. 1236, and Hakozaki et al., p. 1243.

Experiment 1


Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/14

Curator: Hamza

Revision editor(s): Hamza, Scholastica, Folakunmi, Victoria

Subjects

Location of subjects
China
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
Digestive System Carcinoma carcinoma of digestive system,carcinoma of the gastrointestinal system,digestive system carcinoma,gastrointestinal carcinoma,gastrointestinal carcinoma (disease),gastrointestinal system carcinoma,Digestive System Carcinoma,digestive System Carcinoma
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Non-responders to anti–PD-1/PD-L1 immunotherapy
Group 1 name Corresponds to the case (exposed) group for case-control studies
Responders to anti–PD-1/PD-L1 immunotherapy
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Patients with stage 3 or stage 4 gastrointestinal cancer who achieved an objective response (Partial Responders/Stable Disease) lasting at least 3 months upon treatment start with anti–PD-1/PD-L1 immunotherapy.
Group 0 sample size Number of subjects in the control (unexposed) group
29
Group 1 sample size Number of subjects in the case (exposed) group
45
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
None

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).
raw counts
Statistical test
Zero-Inflated Negative Binomial Regression
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)?
No

Alpha Diversity

Inverse Simpson Modification of Simpsons index D as 1/D to obtain high values in datasets of high diversity and vice versa
unchanged

Signature 1

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/15

Curator: Hamza

Revision editor(s): Hamza, Scholastica

Source: Fig. 3A, Supp. Table S6

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 Immunotherapy in all 74 patients with Gastrointestinal Cancer

Abundance in Group 1: increased abundance in Responders to anti–PD-1/PD-L1 immunotherapy

NCBI Quality ControlLinks
Dialister
Lachnospira
Parabacteroides
CAG-352CAG-352
Prevotella_2Prevotella_2
Ruminiclostridium_5Ruminiclostridium_5
Ruminococcus_2Ruminococcus_2
Ruminiclostridium_9Ruminiclostridium_9
uncultured Lachnospiraceae bacterium
uncultured Oscillospiraceae bacterium

Revision editor(s): Hamza, Scholastica

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/15

Curator: Hamza

Revision editor(s): Hamza, Scholastica

Source: Fig. 3A, Supp. Table S6

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 Immunotherapy in all 74 patients with Gastrointestinal Cancer

Abundance in Group 1: decreased abundance in Responders to anti–PD-1/PD-L1 immunotherapy

NCBI Quality ControlLinks
Bacteroides
Catenibacterium
Hungatella
Ruminococcus_2Ruminococcus_2
Ruminococcaceae NK4A214 groupRuminococcaceae NK4A214 group
uncultured Oscillospiraceae bacterium

Revision editor(s): Hamza, Scholastica

Experiment 2


Reviewed Marked as Reviewed by Folakunmi on 2024-4-10

Curated date: 2024/03/29

Curator: Scholastica

Revision editor(s): Scholastica, Folakunmi, Victoria

Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Colorectal cancer cancer of colorectum,cancer of large bowel,cancer of large intestine,cancer of the large bowel,colon cancer,colorectal cancer,colorectum cancer,CRC,large intestine cancer,malignant colorectal neoplasm,malignant colorectal tumor,malignant colorectum neoplasm,malignant large bowel neoplasm,malignant large bowel tumor,malignant large intestine neoplasm,malignant large intestine tumor,malignant neoplasm of colorectum,malignant neoplasm of large bowel,malignant neoplasm of large intestine,malignant neoplasm of the large bowel,malignant neoplasm of the large intestine,malignant tumor of large bowel,malignant tumor of large intestine,malignant tumor of the large bowel,malignant tumor of the large intestine,Colorectal cancer
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Non-responders (colorectal cancer - CRC)
Group 1 name Corresponds to the case (exposed) group for case-control studies
Responders (colorectal cancer - CRC)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Patients with colorectal cancer (CRC) who achieved an objective response (Partial Responders/Stable Disease) lasting at least 3 months upon treatment start with anti–PD-1/PD-L1 immunotherapy.
Group 0 sample size Number of subjects in the control (unexposed) group
7
Group 1 sample size Number of subjects in the case (exposed) group
12

Lab analysis

Statistical Analysis

Alpha Diversity

Inverse Simpson Modification of Simpsons index D as 1/D to obtain high values in datasets of high diversity and vice versa
unchanged

Signature 1

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/29

Curator: Scholastica

Revision editor(s): Scholastica

Source: Fig. 3B, Supp. Table S7

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 immunotherapy in patients with Colorectal Cancer (CRC)

Abundance in Group 1: increased abundance in Responders (colorectal cancer - CRC)

NCBI Quality ControlLinks
Bacteroides
Dialister
Flavonifractor
Lachnoclostridium
Lachnospira
Parabacteroides
Ruminococcaceae bacterium UCG-005
Lachnospiraceae_AC2044_groupLachnospiraceae_AC2044_group
Ruminococcus_2Ruminococcus_2
uncultured Lachnospiraceae bacterium

Revision editor(s): Scholastica

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/29

Curator: Scholastica

Revision editor(s): Scholastica

Source: Fig. 3B, Supp. Table S7

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 immunotherapy in patients with Colorectal Cancer (CRC)

Abundance in Group 1: decreased abundance in Responders (colorectal cancer - CRC)

NCBI Quality ControlLinks
Bacteroides
Bifidobacterium
Lachnoclostridium
Odoribacter
Oscillibacter
Parabacteroides
Subdoligranulum
Coprococcus_2Coprococcus_2

Revision editor(s): Scholastica

Experiment 3


Reviewed Marked as Reviewed by Folakunmi on 2024-4-10

Curated date: 2024/03/30

Curator: Scholastica

Revision editor(s): Scholastica, Folakunmi, Victoria

Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Esophageal carcinoma cancer of esophagus,cancer of oesophagus,cancer of the esophagus,carcinoma of esophagus,carcinoma of oesophagus,carcinoma of the esophagus,esophageal cancer,esophageal cancer, NOS,esophageal carcinoma,esophagus carcinoma,Esophageal carcinoma
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Non-responders (esophageal carcinoma)
Group 1 name Corresponds to the case (exposed) group for case-control studies
Responders (esophageal carcinoma)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Patients with esophageal carcinoma who achieved an objective response (Partial Responders/Stable Disease) lasting at least 3 months upon treatment start with anti–PD-1/PD-L1 immunotherapy.
Group 0 sample size Number of subjects in the control (unexposed) group
6
Group 1 sample size Number of subjects in the case (exposed) group
8

Lab analysis

Statistical Analysis

Alpha Diversity

Inverse Simpson Modification of Simpsons index D as 1/D to obtain high values in datasets of high diversity and vice versa
unchanged

Signature 1

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/30

Curator: Scholastica

Revision editor(s): Scholastica

Source: Fig. 3C, Supp. Table S8

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 Immunotherapy in esophageal carcinoma cancer patients

Abundance in Group 1: increased abundance in Responders (esophageal carcinoma)

NCBI Quality ControlLinks
Bacteroides
Dialister
Lachnospiraceae bacterium NK4A136
Paraprevotella
Parasutterella
Phascolarctobacterium
Prevotella_9Prevotella_9
Ruminococcus_2Ruminococcus_2
uncultured Lachnospiraceae bacterium

Revision editor(s): Scholastica

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/30

Curator: Scholastica

Revision editor(s): Scholastica

Source: Fig. 3C, Supp. Table S8

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 Immunotherapy in esophageal carcinoma cancer patients

Abundance in Group 1: decreased abundance in Responders (esophageal carcinoma)

NCBI Quality ControlLinks
Bacteroides
Clostridium
Hungatella
Lachnospira
Lactobacillus
Marvinbryantia
Ruminococcaceae NK4A214 groupRuminococcaceae NK4A214 group
uncultured Oscillospiraceae bacterium

Revision editor(s): Scholastica

Experiment 4


Reviewed Marked as Reviewed by Folakunmi on 2024-4-10

Curated date: 2024/03/30

Curator: Scholastica

Revision editor(s): Scholastica, Folakunmi, Victoria

Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Gastric cancer Ca body - stomach,ca greater curvature of stomach,Ca lesser curvature - stomach,cancer of stomach,gastric cancer,gastric cancer, intestinal,gastric neoplasm,malignant gastric neoplasm,malignant gastric tumor,malignant neoplasm of body of stomach,malignant neoplasm of lesser curve of stomach,malignant neoplasm of stomach,malignant neoplasm of the stomach,malignant stomach neoplasm,malignant tumor of body of stomach,malignant tumor of greater curve of stomach,malignant tumor of lesser curve of stomach,malignant tumor of stomach,malignant tumor of the stomach,stomach cancer,Gastric cancer
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Non-responders (gastric cancer)
Group 1 name Corresponds to the case (exposed) group for case-control studies
Responders (gastric cancer)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Patients with gastric cancer who achieved an objective response (Partial Responders/Stable Disease) lasting at least 3 months upon treatment start with anti–PD-1/PD-L1 immunotherapy.
Group 0 sample size Number of subjects in the control (unexposed) group
8
Group 1 sample size Number of subjects in the case (exposed) group
15

Lab analysis

Statistical Analysis

Alpha Diversity

Inverse Simpson Modification of Simpsons index D as 1/D to obtain high values in datasets of high diversity and vice versa
unchanged

Signature 1

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/30

Curator: Scholastica

Revision editor(s): Scholastica

Source: Fig. 3D, Supp. Table S9

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 immunotherapy in gastric cancer patients

Abundance in Group 1: increased abundance in Responders (gastric cancer)

NCBI Quality ControlLinks
Prevotella_9Prevotella_9
Bifidobacterium
Prevotella_2Prevotella_2
Lachnospira
Bacteroides
Ruminococcaceae bacterium UCG-005
Agathobacter

Revision editor(s): Scholastica

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/30

Curator: Scholastica

Revision editor(s): Scholastica

Source: Fig. 3D, Supp. Table S9

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 immunotherapy in gastric cancer patients

Abundance in Group 1: decreased abundance in Responders (gastric cancer)

NCBI Quality ControlLinks
Agathobacter
Bacteroides
Bifidobacterium
Butyricimonas
Megamonas
uncultured Lachnospiraceae bacterium

Revision editor(s): Scholastica

Experiment 5


Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/30

Curator: Scholastica

Revision editor(s): Scholastica, Victoria

Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Digestive System Carcinoma carcinoma of digestive system,carcinoma of the gastrointestinal system,digestive system carcinoma,gastrointestinal carcinoma,gastrointestinal carcinoma (disease),gastrointestinal system carcinoma,Digestive System Carcinoma,digestive System Carcinoma
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Responders to anti–PD-1/PD-L1 immunotherapy
Group 1 name Corresponds to the case (exposed) group for case-control studies
Non-responders to anti–PD-1/PD-L1 immunotherapy
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Patients with stage 3 or stage 4 gastrointestinal cancer who did not achieved an objective response (Partial Responders/Stable Disease) lasting at least 3 months upon treatment start with anti–PD-1/PD-L1 immunotherapy.
Group 0 sample size Number of subjects in the control (unexposed) group
25

Lab analysis

Sequencing type
WMS
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
Not specified

Statistical Analysis

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


Signature 1

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/30

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supp. Table S10

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 immunotherapy in patients with Gastrointestinal Cancer (Responders, n=25; Non-responders, n=15)

Abundance in Group 1: increased abundance in Non-responders to anti–PD-1/PD-L1 immunotherapy

NCBI Quality ControlLinks
Latilactobacillus curvatus
Catenibacterium mitsuokai
Dialister succinatiphilus
unclassified Yersinia (in: enterobacteria)

Revision editor(s): Scholastica

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2024-4-9

Curated date: 2024/03/30

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supp. Table S10

Description: Differential abundance between responders and non-responders to Anti–PD-1/PD-L1 immunotherapy in patients with Gastrointestinal Cancer (Responders, n=25; Non-responders, n=15)

Abundance in Group 1: decreased abundance in Non-responders to anti–PD-1/PD-L1 immunotherapy

NCBI Quality ControlLinks
Agathobacter rectalis
Clostridium perfringens
Eubacterium ramulus
Limosilactobacillus mucosae
Parabacteroides distasonis
Rothia dentocariosa
Streptococcus anginosus
Streptococcus sanguinis
Streptococcus vestibularis
unclassified Granulicatella
Coprococcus catus
Dorea longicatena
Erysipelotrichaceae bacterium 6_1_45
Akkermansia muciniphila

Revision editor(s): Scholastica