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THE EFFECT OF GUT MICROBIOTA ON IMMUNE CHECKPOINT INHIBITORS IN THE TREATMENT OF PAN-CANCER AND NOVEL MICROBIAL BIOMARKERS FOR PREDICTING THERAPEUTIC RESPONSE
Date
May 20, 2024
Background & aims:
The gut microbiota is closely related to cancer patient response to immune checkpoint inhibitors (ICI). However, there are inconsistencies in species affecting ICI efficacy, whilst the role of non-bacterial microbes in immunotherapy remains elusive. Here, we evaluated the association of trans-kingdom microbes with ICI by multi-cohort pan-cancer analyses.
Methods:
We retrieved fecal metagenomes from 1,359 ICI recipients (601 responders, 758 non-responders) with four different cancers (metastatic melanoma (MM), non-small cell lung carcinoma (NSCLC), renal cell cancer (RCC), hepatocellular carcinoma) from 12 published datasets. Trans-kingdom microbiota composition and microbial interaction were analyzed. The performance of microbial biomarkers to predict ICI response was assessed by logistic regression and random forest. Signature responder-associated microbial species were functionally examined in vitro and in mice.
Results:
Multi-cohort analysis revealed that the composition of trans-kingdom gut microbiota (bacteria, eukaryotes, virus, and archaea) was significantly different between ICI responders and non-responders in pan-cancer. We identified microbes consistently enriched, including bacteria (Faecalibacterium prausnitzii, Coprococcus comes) and eukaryotes (Nemania serpens, Hyphopichia pseudoburtonii) or depleted bacterium Hungatella hathewayi in responders of ≥ 2 cancer types or from ≥ 3 cohorts. Responder-associated species in each cancer type were also revealed, such as F. prausnitzii for patients with MM and 6 microbial species in NSCLC (e.g., bacterium Candidatus Gastranaerophilales bacterium MH-37, eukaryote Aspergillus tamarii, virus crAssphage cr127-1), of which their abundances were correlated with better survival of patients. Functional validation confirmed that these signature species influenced ICI efficacy by modulating CD8+ T cell activity in vitro and in mice. Moreover, panels of trans-kingdom microbial biomarkers (bacteria and eukaryotes) showed great performance in predicting ICI response in patients from the discovery and two validation cohorts (MM: AUROC = 72.27-80.19%; NSCLC: AUROC = 72.70-87.98%; RCC: AUROC = 83.33-89.58%).
Conclusion:
This study identified trans-kingdom microbial signatures associated with ICI in pan-cancer and in specific cancer types, which were further confirmed in vitro and in mice. Trans-kingdom microbial biomarkers are potential predictors of ICI response in cancer patients.
The gut microbiota is closely related to cancer patient response to immune checkpoint inhibitors (ICI). However, there are inconsistencies in species affecting ICI efficacy, whilst the role of non-bacterial microbes in immunotherapy remains elusive. Here, we evaluated the association of trans-kingdom microbes with ICI by multi-cohort pan-cancer analyses.
Methods:
We retrieved fecal metagenomes from 1,359 ICI recipients (601 responders, 758 non-responders) with four different cancers (metastatic melanoma (MM), non-small cell lung carcinoma (NSCLC), renal cell cancer (RCC), hepatocellular carcinoma) from 12 published datasets. Trans-kingdom microbiota composition and microbial interaction were analyzed. The performance of microbial biomarkers to predict ICI response was assessed by logistic regression and random forest. Signature responder-associated microbial species were functionally examined in vitro and in mice.
Results:
Multi-cohort analysis revealed that the composition of trans-kingdom gut microbiota (bacteria, eukaryotes, virus, and archaea) was significantly different between ICI responders and non-responders in pan-cancer. We identified microbes consistently enriched, including bacteria (Faecalibacterium prausnitzii, Coprococcus comes) and eukaryotes (Nemania serpens, Hyphopichia pseudoburtonii) or depleted bacterium Hungatella hathewayi in responders of ≥ 2 cancer types or from ≥ 3 cohorts. Responder-associated species in each cancer type were also revealed, such as F. prausnitzii for patients with MM and 6 microbial species in NSCLC (e.g., bacterium Candidatus Gastranaerophilales bacterium MH-37, eukaryote Aspergillus tamarii, virus crAssphage cr127-1), of which their abundances were correlated with better survival of patients. Functional validation confirmed that these signature species influenced ICI efficacy by modulating CD8+ T cell activity in vitro and in mice. Moreover, panels of trans-kingdom microbial biomarkers (bacteria and eukaryotes) showed great performance in predicting ICI response in patients from the discovery and two validation cohorts (MM: AUROC = 72.27-80.19%; NSCLC: AUROC = 72.70-87.98%; RCC: AUROC = 83.33-89.58%).
Conclusion:
This study identified trans-kingdom microbial signatures associated with ICI in pan-cancer and in specific cancer types, which were further confirmed in vitro and in mice. Trans-kingdom microbial biomarkers are potential predictors of ICI response in cancer patients.
Presenter
Speakers
The Chinese University of Hong Kong
Tracks
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