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GM influences the effectiveness and side effects of cancer therapies, especially immunotherapy. Research shows that bacteria producing short-chain fatty acids (SCFAs), Akkermansia muciniphila, and certain Lachnospiraceae and Ruminococcaceae families improve responses to immune checkpoint inhibitors (ICIs). Dysbiosis and immunosuppressive bacteria correlate with poor treatment outcomes and adverse immune events. Modifying GM through probiotics, prebiotics, fecal microbiota transplantation, and diet could enhance immunotherapy, but standardized clinical protocols are not yet established.
The gut microbiota significantly influences immune responses and the efficacy of Immune Checkpoint Inhibitors (ICIs).
The detection of immunogenic bacterial peptides in melanoma as well as glioblastoma tumors and the evidence that ICI therapy can induce the translocation of gut bacteria indicate that a deeper mechanistic understanding of the interplay between the gut microbiome and host immunity in the context of immunotherapy is an essential step toward precise clinical interventions.
The antitumor efficacy of cancer immunotherapy can correlate with the presence of certain bacterial species within the gut microbiome. However, many of the molecular mechanisms that influence the host response to immunotherapy remain elusive.
Research has shown that early foundational studies in both preclinical models and clinical cohorts have identified variations in the taxonomic composition of the gut microbiome and dietary fiber intake, which are associated with the response to immune checkpoint blockade (ICB) and immune-related toxicity. Dietary fiber and probiotics affect the gut microbiome, which in turn impacts the response to melanoma immunotherapy. The association between gut microbiota signatures and toxicity to combined CTLA-4 and PD-1 blockade is evident. The gut microbiome affects the effectiveness of PD-1–based immunotherapy in treating epithelial tumors.
Improving the relationship between gut microbiota and the response to anti-CTLA-4 and anti-PD-1 immunotherapy can enhance cancer treatment outcomes.
The use of Antibiotics (J01), whether before or after starting immune checkpoint inhibitor therapy, significantly reduces the effectiveness of this treatment in patients with advanced cancer.
Lactic acid bacteria (LAB) in the human gut enhance immunotherapy. The gut microbiota boosts the effectiveness of PD-1-based immunotherapy against epithelial tumors. The commensal microbiome improves anti-PD-1 efficacy in metastatic melanoma patients. Microbiome-derived inosine influences the response to checkpoint inhibitor immunotherapy.
The activity of reducing tumor growth by Immune checkpoint inhibitors (ICIs) necessitates the presence of a specific set of bacteria in the gut.
In 2018, studies on immune checkpoint inhibitors (ICI) in cancer treatment reported positive outcomes, confirming earlier pre-clinical research. These studies, focusing on epithelial tumors and hematological malignancies, emphasized the importance of gut microbiome diversity in enhancing ICI response and patient survival
The immune anticancer activity of Anti-CTLA-4 / CTLA-4 antibodies and/or Anti-PD-1 antibodies / PD-1 inhibitors / Anti-PD-L1 antibodies / PD-L1 inhibitors is lost when immunogenic gut bacteria are absent.
In the last five years, research has revealed that the makeup of the gut microbiota significantly affects the success of anticancer immunosurveillance. This, in turn, enhances the therapeutic effectiveness of immune-checkpoint inhibitors that target proteins like cytotoxic T lymphocyte protein 4 (CTLA-4) or the programmed cell death protein 1 (PD-1)–programmed cell death 1 ligand 1 (PD-L1) axis, as well as the efficacy of immunogenic chemotherapies. Certain bacteria, including Akkermansia muciniphila, Bacteroides fragilis, Bifidobacterium spp., and Faecalibacterium spp. have been linked to positive anticancer immune responses in both preclinical tumor models and cancer patients. Notably, these bacteria also appear to positively impact overall health, thereby decreasing the occurrence of metabolic disorders and various chronic inflammatory diseases.
The immune checkpoint blockade causes the movement of gut microbiota , which enhances antitumor immunity outside the intestines
Despite the strong correlation between the gut microbiome and checkpoint inhibitor therapy outcomes, the exact interactions between specific bacterial species or their products and immune cells remain unclear. It is doubtful whether a fully generalizable mechanism can explain all microbial associations with clinical outcomes
Microbiota can influence the response to Immune Checkpoint Inhibitors (ICIs) through multiple mechanisms, including:
These factors converge to enhance Type 1 immune response against the tumor, particularly in the context of immune checkpoint blockade therapy
A high-fiber diet changed the microbiota. This activated the IFN-I-NK cell-DC axis in tumors. It also made immune checkpoint blockade work better.
Impaired intestinal barrier function due to Immune Checkpoint Inhibitors (ICIs) Therapy facilitates the systemic translocation of inosine, leading to Adenosine A2A receptor -dependent activation of anti-tumor CD4+ Th1 cells, causing tumor shrinkage
Other proposed mechanisms include T cell priming and activation mediated by dendritic cells upon presentation of Microbial associated molecular patterns (MAMPs) present in the gut or from systemic circulation or increased pro-inflammatory cytokines and microbial metabolites
Fessler et al. 2019 J. ImmunoTher. Cancer 7: 108
A common pathway among the beneficial taxa involves the activation of dendritic cells (DC), induction of CD4+ and CD8+ T-cells, an increase in pro-inflammatory T helper 17 cell (Th17) and associated interleukins (e.g., Interleukin-17 Family / Interleukin-17 (IL-17), Interleukin-12 (IL-12 p70)), and a decrease in Interleukin-10 (IL-10) and regulatory T cells (Tregs)
The differential response of patients to ICIs, in terms of both efficacy and tolerability, can be linked to the intrinsic individual diversity of the immune system and other host-related factors
Certain species enhance the antitumor effectiveness of Immune checkpoint inhibitors (ICIs) by promoting the functions of DCs and CD8+ T cells while inhibiting Treg cells.
The metabolite of dietary tryptophan, released by intratumoral Limosilactobacillus reuteri aids in the treatment with immune checkpoint inhibitors.
Reports have identified specific spore-forming taxa, including those in the Firmicutes phyla and the Ruminococcaceae family, as being associated with an improved response.
A recent study isolated 11 bacterial strains from healthy human donor feces capable of inducing large numbers of IFN-gamma+ CD8+ T cells in the intestine. When used in combination with immune checkpoint inhibitors, these bacterial strains could inhibit tumor growth
Certain bacterial species have been associated with improved clinical outcomes in patients undergoing ICI therapy:
Akkermansia muciniphila, Enterococcus hirae, Phascolarctobacterium, and Bifidobacterium species were more abundant in patients with prolonged progression-free survival
References
Vetizou & Trinchieri 2018 Cell Res. 28(3): 263-264
Inosine, produced by gut bacteria like Bifidobacterium pseudolongum or Akkermansia muciniphila, improves the effectiveness of Immune Checkpoint Inhibitors (ICIs) in mouse models
References
The human gut microbiota has been associated with clinical responses to anti–PD-1/PD-L1 immunotherapy in melanoma, NSCLC, and RCC
Several studies have analyzed the differences between immunotherapy-sensitive and immunotherapy-resistant cohorts, showing that specific gut microbiota profiles are closely associated with treatment effects. Interventional gut microbiota modulation has been shown to enhance efficacy and relieve resistance during immunotherapy treatment
Certain studies have demonstrated that the gut microbiota serves a key role in regulating a patient's response to immunotherapy
In pre-clinical models, the absence of an intact gut microbiome negatively impacted ICI efficacy
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Antibiotics inhibited the clinical benefit of Immune Checkpoint Blockade / Immune Checkpoint Inhibitors (ICIs) in patients with advanced cancer
Responder microbiomes often have the Ruminococcaceae family and Faecalibacterium genus. Non-responders have more species from the Bacteroidales order.
Recent studies have contributed to the idea that the gut microbiome determines the so-called ‘immune-cancer set point’, including the capacity of ICI to stimulate the immune system to kill cancer cells
An abundance of Eubacterium limosum and Blautia is associated with decreased relapse and reduced mortality
Vetizou & Trinchieri 2018 Cell Res. 28(3): 263-264
Butyrate producers are abundant in responder patients, and species that indirectly contribute to butyrate production by cross-feeding are also prevalent
Studies show different SCFA expressions in immunotherapy responders vs. non-responders
Gut microbes modulate overall immunity and immunotherapy response, as shown in pre-clinical models and human studies
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analyzed the metagenomes of 680 stool samples from seven studies and identified Faecalibacterium prausnitzii, Eubacterium rectale, and three Bifidobacterium species (Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium longum) as most beneficial.
This outcome confirms the importance of direct and indirect butyrate production, where Bifidobacteria stimulate butyrate production by Faecalibacterium prausnitzii and Eubacterium rectale, and vice versa
The gut microbiota has emerged as a biomarker of response to ICIs and a critical determinant of the development of immune-related adverse events (irAEs)
It directly affects both the efficacy and toxicity of ICIs
Pezo et al. 2019 Therap Adv Gastroenterol 12: 1-10
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The relevance of the gut microbiota has been demonstrated as both a marker and an adjuvant for enhancement of clinical response to treatment with checkpoint inhibitors
Baseline gut microbiota enriched with Faecalibacterium and other Firmicutes is associated with beneficial clinical response to ipilimumab and more frequent occurrence of ipilimumab-induced colitis
Routy et al. compared the therapeutic effect of monotherapy with PD-1 antibodies or combination therapy of anti-PD-1 and anti-CTLA-4 in specific Pathogen-free mice that were treated with a combination of antibiotics, as well as untreated mice.
Intestinal dysbiosis contributes to primary resistance towards immune checkpoint inhibitors (ICIs)
They found that a biotic treatment compromised the anti-tumor effects of ICI and decreased the survival rate of the mice.
The gut microbiota from patients with advanced Melanoma (cutaneous), Non-small-cell lung cancer (NSCLC), and Renal cell carcinoma (RCC) who failed ICI treatment differed in its composition from those who responded
More high-performance studies are needed to thoroughly assess the clinical significance of antibiotic-induced changes in gut microbiota and their effects on colorectal cancer (CRC) immunotherapy
Preclinical data suggest that modulation of the microbiota could become a novel strategy for improving the efficacy of immunotherapy
Exercise is beneficial to physical health, and it also helps to promote efficacy following immunotherapy. In a recent paper published in Cell, Phelps et al. identified that the gut microbiota plays a critical role in how exercise improves checkpoint inhibitor efficacy in melanoma.
A longitudinal study on patients with unresectable melanoma undergoing anti-PD-1 therapy revealed that patient responses to immune checkpoint inhibitors (ICIs) are linked to changes in gut microbiota. Complete responders exhibited stable microbiota functions, validated through external cohorts and experimental methods. The study identified MHC class I-restricted peptides from Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens. FLach-reactive CD8+ T cells were present before ICI therapy in complete responders, and FLach peptides enhanced antitumor immunity. These findings highlight the prognostic value of microbial functions and the potential of microbial peptides in improving antitumor responses
The commensal microbiome is linked to the effectiveness of anti–PD-1 treatment in patients with metastatic melanoma. Dietary fiber and probiotics affect the gut microbiome, which in turn impacts the response to melanoma immunotherapy. The gut microbiota in therapy with Immune Checkpoint Inhibitors (ICIs) differs between responding (R) and non-responding (nR) patients. Fecal microbiota transplantation (FMT) from responding or healthy donors has shown the potential to extend the benefits of ICIs to more patients, including those with refractory melanoma. However, variability between studies presents challenges, and the exclusive focus on response outcomes might overlook important differences in the gut.
We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals could be transferred by fecal microbiota transplantation
Patients with cutaneous melanoma treated with anti-PD-1 antibodies/PD-1 inhibitors have shown improved outcomes when their gut microbiota exhibits increased diversity. Research by Gopalakrishnan et al. highlights that a higher diversity of the gut microbiota and the presence of specific bacteria, such as Ruminococcaceae and Faecalibacterium, are associated with longer progression-free survival and a better response to immune checkpoint inhibitors (ICIs) in melanoma patients. Conversely, a lower diversity of gut microbiota and the presence of other bacteria, like Bacteroidetes, correlate with poorer outcomes. Supporting studies using gnotobiotic mice have demonstrated that different bacterial groups can distinctly modulate the immune system. Patients with a "favorable" gut microbiota, characterized by high diversity and an abundance of Ruminococcaceae, Oscillospiraceae, and Faecalibacterium, exhibit enhanced systemic and anti-tumor immune responses. This suggests that the composition of the gut microbiota plays a crucial role in the effectiveness of melanoma treatments involving PD-1 inhibitors.
Gut dysbiosis was associated with resistance to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma and other solid tumors
In metastatic melanoma patients who received Anti-PD-1 Antibodies / Anti-PD-1 Checkpoint Inhibitors, Faecalibacterium prausnitzii associated with higher gut bacterial diversity and clinical response and Anaerotruncus colihominis, Bacteroides thetaiotaomicron, Escherichia coli with lower gut bacterail diversity and lower clinical response have been seen
The group found that patients who responded to anti-PD-1 therapy had enrichment of Bifidobacterium longum, Collinsella aerofaciens and Enterococcus faecium in baseline fecal samples
Regarding the composition differences between responder and non-responder microbiomes, the Ruminococcaceae family and the Faecalibacterium genus are most common among responders, in contrast to species from the Bacteroidales order, which are abundant in the stool of ICI non-responders were present
In metastatic melanoma patients who received Anti-PD-1 Antibodies / Anti-PD-1 Checkpoint Inhibitors, higher clinical response was associated with higher abundance of Akkermansia muciniphila, Bifidobacterium adolescentis, Bifidobacterium longum, Collinsella aerofaciens, Enterococcus faecium, Klebsiella pneumoniae, Lactobacillus spp., Parabacteroides merdae, Veillonella parvula and lower clinical response with higher abundance of Roseburia intestinalis, Ruminococcus obeum. Further, fecal microbiota transplants (FMT) into gnotobiotic mice revealed that six of these bacteria, particularly Bifidobacterium longum and Lactobacillus species, were associated with slower tumor growth in mouse models
Chaput et al. demonstrated that melanoma patients treated with the anti-CTLA-4 drug, ipilimumab, showed longer survival rates when their baseline microbiota was enriched with the Faecalibacterium genus and other Firmicutes. Conversely, patients with a high abundance of Bacteroidetes experienced less benefit from the therapy
In metastatic melanoma patients who received ipilimumab , Bacteroides spp. associated with less anti-CTLA-4 induced colitis has been seen associated with a lower risk of anti-CTLA-4 induced colitis
Frankel et al. investigated the pre-treatment gut microbiota of patients undergoing dual immune checkpoint inhibitor (ICI) therapy for metastatic melanoma. Their research found that the presence of gut taxa from the Firmicutes phylum and an abundance of Bacteroides thetaiotaomicron were linked to the effectiveness of combined anti-CTLA-4 and anti-PD-1 immunotherapy. In metastatic melanoma patients who received ICIs higher clinical response was associated with the abundance of Bacteroides caccae, Bacteroides thetaiotamicron, Dorea formicogenerans, Faecalibacterium prausnitzii, Holdemania filiformis
Metagenomic shotgun sequencing and unbiased Metabolomic profiling identify specific gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Unbiased shotgun metabolomics revealed high levels of Anacardic Acids in immune checkpoint inhibitor therapy (melanoma) responders
In metastatic melanoma patients who received ipilimumab, Bacteroidaceae, Barnesiellaceae, and Rikenellaceae have been seen as favorable gut bacteria associated with a lower risk of anti-CTLA-4 induced colitis
Melanoma does not respond to CTLA-4 blockade in antibiotic-treated or germ-free mice (GF)
In mice and patients, T cell responses specific for Bacteroides thetaiotaomicron or B. fragilis are associated with the efficacy of Anti-CTLA-4 / CTLA-4 antibodies. Bacteroides fragilis administration, B. fragilis polysaccharides, or B. fragilis-specific T cells successfully rescued the failure of CTLA-4 blockade in melanoma patients.
The gut microbiota of newly diagnosed Colorectal Cancer (CRC) patients impaired the efficacy of anti-PD-1 mAb in tumor-bearing mice.
In mice, Pectin enhanced the efficacy of Anti-PD-1 antibodies / PD-1 inhibitors
In the context of gastrointestinal cancers, researchers have found in fecal samples an increase in the ratio of Prevotella and Bacteroides. This elevated ratio is observed in patients who respond well to treatments with Anti-PD-1 antibodies / PD-1 inhibitors or Anti-PD-L1 antibodies / PD-L1 inhibitors. Furthermore, certain short-chain fatty acids (SCFAs) producing bacteria are linked to a positive response to these treatments. These bacteria include Eubacterium, Lactobacillus, and Streptococcus. The presence of these SCFA-producing bacteria is associated with better outcomes in patients with various types of gastrointestinal cancers under anti–PD-1/PD-L1 therapy.
In metastatic bladder cancer, Non-Small-Cell Lung Cancer (NSCLC), Renal Cell Carcinoma (RCC) patients who received Anti-PD-1 antibodies / PD-1 inhibitors or Anti-PD-L1 Antibodies / Inhibitors , higher clinical response was associated with higher abundance of Akkermansia muciniphila, Alistipes spp., Eubacterium spp., Ruminococcus spp. and with lower abundance of Bifidobacterium adolescentis, Bifidobacterium longum, Parabacteroides distasonis
The immune anticancer activity of anti-CTLA-4 and/or anti-PD-1/PD-L1 was lost in the absence of immunogenic gut bacteria
In a study conducted by Derosa et al. in 2018, involving 249 patients with non-small cell lung cancer (NSCLC) and 121 patients with renal cell carcinoma (RCC), the researchers investigated the effects of antibiotic use within one month prior to the start of immune checkpoint inhibitors (ICI) in either first- or second-line treatment settings. The findings indicated that the clinical outcomes were worse for those who had taken antibiotics.
The group decided to set the cut-off at two months, instead of one month, before starting immune checkpoint inhibitors (ICI) to determine whether patients should be included in the antibiotic or non-antibiotic groups. They discovered that the effect of antibiotics on the clinical efficacy of ICI was less pronounced.
In metastatic Non-Small-Cell Lung Cancer (NSCLC) patients who received Ipilimumab, higher clinical response was associated with the abundance of B. fragilis, Bacteroides thetaiotaomicron
Research using transplantable mouse models of various cancers, such as colon cancer (MC-38), fibrosarcoma (MCA-205), non-small cell lung cancer (NSCLC) (LLC), melanoma (RET), and renal cell carcinoma (RCC) (RENCA), has shown that certain gut bacteria are important for cancer treatment. Specifically, the presence of Bacteroides fragilis and Bifidobacterium in the intestines helps make treatments that block CTLA-4 and PD-1 more effective in reducing tumor growth.
see also:
Adenosine A2A receptor & Inosine
Adoptive T Cell Therapy / CAR-T & Gut microbiota
Akkermansia muciniphila & Immune Checkpoint Inhibitors (ICIs)
Anti-CTLA-4 / CTLA-4 antibodies & Gut microbiota
Anti-PD-1 antibodies / PD-1 inhibitors & Gut microbiota
Anti-PD-1 Antibodies / PD-1 Inhibitors & Melanoma (cutaneous)
Antibiotics & Immune Checkpoint Inhibitors (ICIs)
Anti–PD-1 Resistance
Anti-PD-1 antibodies / PD-1 inhibitors + Fecal Microbiota Transplantation (FMT) & Gastrointestinal cancers
Bifidobacterium pseudolongum & Inosine
Biomarker & Immune checkpoint inhibitors (ICIs)
Cancer Immunotherapy / Immuno-Oncology & Fusobacterium nucleatum
Cancer Immunotherapy / Immuno-Oncology & Gut microbiota
Cancer / Tumors & Gut microbiota
Cancer microbiome / Tumor microbiota
CD4+ Th1 Cells & Inosine
Cytotoxic T cell (CTL) & Gut microbiota
Gut microbiota & Pharmaceuticals / Medication
Drugs / Medications & Metabolic activities / Metabolism
Enterococcus & Immune checkpoint inhibitors (ICIs)
Extraintestinal Manifestations
Faecalibacterium prausnitzii & Immune Checkpoint Inhibitors (ICIs)
Fecal Microbiota Transplantation (FMT) + Immune Checkpoint Inhibitors (ICIs)
Fecal Microbiota Transplantation (FMT) & Immune Checkpoint Inhibitor-Associated Colitis / Intestinal inflammation (ICIAC)
Fecal Microbiota Transplantation (FMT) & Immune Checkpoint Inhibitors (ICIs) Therapy (to improve)
Fecal Microbiota Transplantation (FMT) & Melanoma (cutaneous)
Fecal Microbiota Transplantation (FMT) + Nivolumab & Melanoma (cutaneous)
Fecal Microbiota Transplantation (FMT) + Pembrolizumab & Melanoma (cutaneous)
Human gut mycobiome & Immune checkpoint inhibitors (ICIs)
Immune checkpoint inhibitors (ICIs) & Indole-3-propionic acid / Indole-3-Propionate (IPA)
Immune checkpoint inhibitors (ICIs) + Probiotics (living agents) & Gastric cancer / Gastric adenocarcinoma / Stomach cancer
Immune checkpoint inhibitors (ICIs) + Probiotics (living agents) & Gastroesophageal Junction Adenocarcinoma (GEJ Adenocarcinoma)
Immune checkpoint inhibitors (ICIs) + Probiotics (living agents) & Melanoma (cutaneous)
Immune checkpoint inhibitors (ICIs) + Probiotics (living agents) & Non-small-cell lung cancer (NSCLC)
Immune checkpoint inhibitors (ICIs) + Probiotics (living agents) & Renal cell carcinoma (RCC)
Immune Checkpoint Inhibitors (ICIs) Therapy (to improve) & Drugs/Treatments
Cancer microbiome / Tumor microbiome & Melanoma (cutaneous)
Gastrointestinal cancers & Gut microbiota
Immune checkpoint inhibitors & Inosine
Immune Checkpoint Inhibitors (ICIs) & Melanoma (cutaneous)
Gut microbiota & Inosine
Lactobacillus johnsonii
Oat
XXX - Anti-PD-1 antibodies / PD-1 inhibitors + Pectin vs Anti-PD-1 antibodies / PD-1 inhibitors vs Pectin & Colorectal cancer (CRC)