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Source | Lilac Academic In recent years, immune checkpoint inhibitors (ICIs) have brought new hope to cancer patients
.
It has been approved for the clinical treatment of various tumors such as melanoma, kidney cancer, head and neck cancer, and bladder cancer.
It has made breakthroughs in the treatment of lung cancer and is currently the most commonly used immunotherapy regimen
.
However, only a minority of patients have durable responses to immunotherapy, and their primary resistance remains a major obstacle
.
The gut microbiome has emerged as a key factor in shaping tumor immune surveillance and enhancing the efficacy of ICI
.
Camu-camu (CC), also known as acai, is an Amazonian berry rich in vitamin C, anthocyanins, and has been shown to increase the intestinal bacteria A.
muciniphila and Bifidobacterium abundance, exert a protective effect on obesity and related metabolic disorders in mice
.
Recently, Bertrand Routy's team from the Research Center of the University of Montreal in Canada published a research paper entitled: A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiota in the journal Cancer Discovery
.
This study found that camu camu can alter gut microbiota composition and enhance antitumor activity and anti-PD-1 response
.
At the same time, it was found that the chestnut ellagin (castalagin) rich in Camu Camu is the main bioactive molecule that exerts its anti-tumor effect
.
Antitumor activity of Camu camu is dependent on the microbiome and circumvents anti-PD-1 resistance To evaluate the antitumor effect of oral camu camu supplementation, mice inoculated with MCA-205 sarcoma (ICI-sensitive) received camu camu daily Fruit (CC) was orally administered by gavage, and anti-PD-1 or anti-PD-1 control (IsoPD-1) was intraperitoneally injected every 3 days
.
It was found that the therapeutic effects of CC/IsoPD-1 and water/PD-1 were similar compared with water/IsoPD-1, and the combination of CC and PD-1 could further inhibit tumor growth
.
On this basis, the researchers further tested whether the antitumor effect of CC depends on the gut microbiota
.
They performed fecal microbiota transplantation (FMT) in germ-free mice using fecal samples from mice treated with or without CC within 14 days after inoculation of mice with MCA-205 sarcoma and found that only feces from CC-treated mice Transplantation can further improve PD-1 activity
.
These experiments suggest that the antitumor activity of CC is microbe-dependent
.
Camu camu increases microbiome diversity and beneficially alters microbiome composition.
To elucidate the effect of camu camu on gut microbiome composition, the researchers characterized the microbiome in the MCA-205 mouse model treated with CC.
group composition
.
Alpha diversity was increased in the CC-treated group compared to water/IsoPD-1
.
Differential abundance analysis showed a higher proportion of Ruminococcus levels in the CC group compared to the control group
.
Meanwhile, gut microbiome analysis using 16S rRNA sequencing in the E0771 tumor model showed that compared with water/PD-1 controls, Ruminococcus UBA1819, Turicibacter, Parasutterella, Ruminococcus, A.
muciniphila and Christensenellaceae R-7 and Oscillospiraceae UCG-005 all increased
.
Taken together, these results suggest that CC induces changes in gut microbiota composition
.
Antitumor activity of camu camu is dependent on CD8+ T cells and correlated with immunogenic bacterial species Next, we characterized the immune-enhancing effects of CC within tumor-infiltrating lymphocytes (TILs) by flow cytometry
.
In the MCA-205 model without fecal microbiota transplantation, the analysis showed that compared with water/IsoPD-1, in three groups of treatments (CC/IsoPD-1, CC/PD-1 or water/PD-1) showed antitumor activity -1), CD8+/Foxp3+CD4+ T cells increased
.
We further examined subsets of TILs and found that CC/IsoPD-1 increased the proportion of central memory CD8+ T cells compared to water/IsoPD-1
.
To verify that the antitumor activity associated with CC is mediated by CD8+ T cells, we administered an anti-CD8+ monoclonal antibody to deplete CD8+ T cell subsets in MCA-205 mice, concurrently with oral gavage in combination with CC
.
Results showed increased tumor growth in mice treated with CC and anti-CD8+ monoclonal antibody compared to CC/IsoCD8+ (control), suggesting that the microbiome-mediated effects of CC are CD8+ T cell-dependent
.
The polyphenolic substance Castalagin in Camu Camu has anti-tumor effects Next, the bioactive molecules for the microbiome-dependent anti-tumor activity of Camu camu were investigated
.
Using high performance liquid chromatography (HPLC), the original extract was isolated from CC according to its molecular polarity, and it was found that castalagin was associated with the antitumor effect of CC
.
Similar tumor-suppressive effects were obtained with castalagin alone or in combination with PD-1 in MCA-205 and E0711 mouse tumor models
.
Next, the researchers analyzed the effect of castalagin on the microbiome of SPF mice using the 16S rRNA microbiome in the MCA-205 model
.
The analysis showed that castalagin led to the enrichment of Ruminococccaceae UBA1819, A.
muciniphila, Ruminococcus, Blautia and Alistipes
.
Systemic immune effects of castalagin are CD8+ T-cell-dependent Next, we examined whether castalagin could also reproduce the systemic immune response to CC
.
First, experiments in MCA-205 mice confirmed that castalagin upregulates TCM CD8+ T cells in mouse TILs
.
Second, immunofluorescence staining of tumors further showed that the ratio of CD8+/CD4+Foxp3+ T cells was increased in the castalagin/IsoPD-1 group compared with water/IsoPD-1
.
Again, tumor transcriptome analysis by RNA-sequencing observed upregulation of relevant gene pathways in the castalagin/IsoPD-1 group compared to the water/IsoPD-1 control group, including antigen processing and presentation, T cell receptor signaling, and The NF-kappa B signaling pathway is associated with an inflamed tumor microenvironment
.
Finally, the researchers observed that the proportion of CFSElow CD8+ T cells in the draining lymph nodes of mice in the castalagin group was lower than that in the control group, corresponding to a higher percentage of killing, which also suggests a CD8+ T cell-dependent mechanism of castalagin
.
Castalagin can circumvent anti-PD-1 resistance Using feces from 4 ATB-treated NR patients with non-small cell lung cancer (taking antibiotics and receiving immunotherapy), transplanted into germ-free mice, tested after fecal transplantation The healing effect of castalagin
.
The results show that castalagin alone exerts antitumor activity and also promotes response to anti-PD-1 therapy
.
Using 16S rRNA to analyze fecal samples from fecal transplant experiments, castalagin treatment increased the relative abundance of Ruminococcus, Alistipes, Christensenellaceae R-7 group and Paraprevotella, while Lachnosclostridium decreased, compared to the water control group
.
Castalagin binds to Ruminococcus brucei and promotes an antitumor response In the gut, castalagin is hydrolyzed to citrus and ellagic acid, which in turn is further converted to urolithin by gut bacteria
.
However, in tumor mouse models, no antitumor effects were observed using its isomer vescalagin or its downstream metabolites citrus, ellagic acid, and urolithin
.
This result suggests that the metabolism of castalagin by gut bacteria may be required for a shift in the composition of the microbiota
.
Fluorescent labeling of castalagin and observation using fluorescence microscopy revealed that castalagin, although not internalized by R.
brucei, was still associated with the cell envelope
.
And the researchers further found that in a germ-free mouse model of MCA-205 tumors, oral supplementation of either Ruminococcus brucei or castalagin alone was ineffective, while the combination of the two showed antitumor activity
.
Summary This study shows for the first time that castalagin, a polyphenolic substance isolated from Camu Camu, can exert antitumor effects by binding to the beneficial gut bacterium Ruminococcus brucei
.
Furthermore, in preclinical ICI resistance models, the use of castalagin re-established anti-PD-1 efficacy and promoted anticancer responses
.
These findings pave the way for future clinical trials using castalagin as an immune checkpoint inhibitor drug in cancer patients to complement this clinical trial, providing new strategies for enhancing and prolonging the efficacy of immunotherapy
.
Paper link: https://doi.
org/10.
1158/2159-8290.
CD-21-0808 is open for reprinting and welcome to forward to Moments and WeChat groups
.
It has been approved for the clinical treatment of various tumors such as melanoma, kidney cancer, head and neck cancer, and bladder cancer.
It has made breakthroughs in the treatment of lung cancer and is currently the most commonly used immunotherapy regimen
.
However, only a minority of patients have durable responses to immunotherapy, and their primary resistance remains a major obstacle
.
The gut microbiome has emerged as a key factor in shaping tumor immune surveillance and enhancing the efficacy of ICI
.
Camu-camu (CC), also known as acai, is an Amazonian berry rich in vitamin C, anthocyanins, and has been shown to increase the intestinal bacteria A.
muciniphila and Bifidobacterium abundance, exert a protective effect on obesity and related metabolic disorders in mice
.
Recently, Bertrand Routy's team from the Research Center of the University of Montreal in Canada published a research paper entitled: A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiota in the journal Cancer Discovery
.
This study found that camu camu can alter gut microbiota composition and enhance antitumor activity and anti-PD-1 response
.
At the same time, it was found that the chestnut ellagin (castalagin) rich in Camu Camu is the main bioactive molecule that exerts its anti-tumor effect
.
Antitumor activity of Camu camu is dependent on the microbiome and circumvents anti-PD-1 resistance To evaluate the antitumor effect of oral camu camu supplementation, mice inoculated with MCA-205 sarcoma (ICI-sensitive) received camu camu daily Fruit (CC) was orally administered by gavage, and anti-PD-1 or anti-PD-1 control (IsoPD-1) was intraperitoneally injected every 3 days
.
It was found that the therapeutic effects of CC/IsoPD-1 and water/PD-1 were similar compared with water/IsoPD-1, and the combination of CC and PD-1 could further inhibit tumor growth
.
On this basis, the researchers further tested whether the antitumor effect of CC depends on the gut microbiota
.
They performed fecal microbiota transplantation (FMT) in germ-free mice using fecal samples from mice treated with or without CC within 14 days after inoculation of mice with MCA-205 sarcoma and found that only feces from CC-treated mice Transplantation can further improve PD-1 activity
.
These experiments suggest that the antitumor activity of CC is microbe-dependent
.
Camu camu increases microbiome diversity and beneficially alters microbiome composition.
To elucidate the effect of camu camu on gut microbiome composition, the researchers characterized the microbiome in the MCA-205 mouse model treated with CC.
group composition
.
Alpha diversity was increased in the CC-treated group compared to water/IsoPD-1
.
Differential abundance analysis showed a higher proportion of Ruminococcus levels in the CC group compared to the control group
.
Meanwhile, gut microbiome analysis using 16S rRNA sequencing in the E0771 tumor model showed that compared with water/PD-1 controls, Ruminococcus UBA1819, Turicibacter, Parasutterella, Ruminococcus, A.
muciniphila and Christensenellaceae R-7 and Oscillospiraceae UCG-005 all increased
.
Taken together, these results suggest that CC induces changes in gut microbiota composition
.
Antitumor activity of camu camu is dependent on CD8+ T cells and correlated with immunogenic bacterial species Next, we characterized the immune-enhancing effects of CC within tumor-infiltrating lymphocytes (TILs) by flow cytometry
.
In the MCA-205 model without fecal microbiota transplantation, the analysis showed that compared with water/IsoPD-1, in three groups of treatments (CC/IsoPD-1, CC/PD-1 or water/PD-1) showed antitumor activity -1), CD8+/Foxp3+CD4+ T cells increased
.
We further examined subsets of TILs and found that CC/IsoPD-1 increased the proportion of central memory CD8+ T cells compared to water/IsoPD-1
.
To verify that the antitumor activity associated with CC is mediated by CD8+ T cells, we administered an anti-CD8+ monoclonal antibody to deplete CD8+ T cell subsets in MCA-205 mice, concurrently with oral gavage in combination with CC
.
Results showed increased tumor growth in mice treated with CC and anti-CD8+ monoclonal antibody compared to CC/IsoCD8+ (control), suggesting that the microbiome-mediated effects of CC are CD8+ T cell-dependent
.
The polyphenolic substance Castalagin in Camu Camu has anti-tumor effects Next, the bioactive molecules for the microbiome-dependent anti-tumor activity of Camu camu were investigated
.
Using high performance liquid chromatography (HPLC), the original extract was isolated from CC according to its molecular polarity, and it was found that castalagin was associated with the antitumor effect of CC
.
Similar tumor-suppressive effects were obtained with castalagin alone or in combination with PD-1 in MCA-205 and E0711 mouse tumor models
.
Next, the researchers analyzed the effect of castalagin on the microbiome of SPF mice using the 16S rRNA microbiome in the MCA-205 model
.
The analysis showed that castalagin led to the enrichment of Ruminococccaceae UBA1819, A.
muciniphila, Ruminococcus, Blautia and Alistipes
.
Systemic immune effects of castalagin are CD8+ T-cell-dependent Next, we examined whether castalagin could also reproduce the systemic immune response to CC
.
First, experiments in MCA-205 mice confirmed that castalagin upregulates TCM CD8+ T cells in mouse TILs
.
Second, immunofluorescence staining of tumors further showed that the ratio of CD8+/CD4+Foxp3+ T cells was increased in the castalagin/IsoPD-1 group compared with water/IsoPD-1
.
Again, tumor transcriptome analysis by RNA-sequencing observed upregulation of relevant gene pathways in the castalagin/IsoPD-1 group compared to the water/IsoPD-1 control group, including antigen processing and presentation, T cell receptor signaling, and The NF-kappa B signaling pathway is associated with an inflamed tumor microenvironment
.
Finally, the researchers observed that the proportion of CFSElow CD8+ T cells in the draining lymph nodes of mice in the castalagin group was lower than that in the control group, corresponding to a higher percentage of killing, which also suggests a CD8+ T cell-dependent mechanism of castalagin
.
Castalagin can circumvent anti-PD-1 resistance Using feces from 4 ATB-treated NR patients with non-small cell lung cancer (taking antibiotics and receiving immunotherapy), transplanted into germ-free mice, tested after fecal transplantation The healing effect of castalagin
.
The results show that castalagin alone exerts antitumor activity and also promotes response to anti-PD-1 therapy
.
Using 16S rRNA to analyze fecal samples from fecal transplant experiments, castalagin treatment increased the relative abundance of Ruminococcus, Alistipes, Christensenellaceae R-7 group and Paraprevotella, while Lachnosclostridium decreased, compared to the water control group
.
Castalagin binds to Ruminococcus brucei and promotes an antitumor response In the gut, castalagin is hydrolyzed to citrus and ellagic acid, which in turn is further converted to urolithin by gut bacteria
.
However, in tumor mouse models, no antitumor effects were observed using its isomer vescalagin or its downstream metabolites citrus, ellagic acid, and urolithin
.
This result suggests that the metabolism of castalagin by gut bacteria may be required for a shift in the composition of the microbiota
.
Fluorescent labeling of castalagin and observation using fluorescence microscopy revealed that castalagin, although not internalized by R.
brucei, was still associated with the cell envelope
.
And the researchers further found that in a germ-free mouse model of MCA-205 tumors, oral supplementation of either Ruminococcus brucei or castalagin alone was ineffective, while the combination of the two showed antitumor activity
.
Summary This study shows for the first time that castalagin, a polyphenolic substance isolated from Camu Camu, can exert antitumor effects by binding to the beneficial gut bacterium Ruminococcus brucei
.
Furthermore, in preclinical ICI resistance models, the use of castalagin re-established anti-PD-1 efficacy and promoted anticancer responses
.
These findings pave the way for future clinical trials using castalagin as an immune checkpoint inhibitor drug in cancer patients to complement this clinical trial, providing new strategies for enhancing and prolonging the efficacy of immunotherapy
.
Paper link: https://doi.
org/10.
1158/2159-8290.
CD-21-0808 is open for reprinting and welcome to forward to Moments and WeChat groups
