Cell sub-issue: Fudan team finds that bacteria are new hope for the treatment of "the most ferocious breast cancer"

Breast cancer is the most common cancer in women, and in 2020 , breast cancer replaced lung cancer and has become the world's number one cancer, according to the latest global cancer burden data released by the WHO International Agency for Research on Cancer ( IARC ) in 2020 .

Breast cancer is the most common cancer in women, and in 2020 , breast cancer replaced lung cancer and has become the world's No.

Most breast cancers have a good prognosis, but about 15% of breast cancers are triple negative breast cancers ( Triple -Negative breast Cancer , TNBC ) .

On March 12 , 2022 , the research group of Prof.

The study found that the microbial metabolite trimethylamine oxide ( TMAO ) can activate anti-tumor immunity and improve the efficacy of triple-negative breast cancer immunotherapy

With the help of multidimensional omics analysis, the study found that in the breast microenvironment of the immunomodulatory subtype ( Immunomodulatory, IM , the group that can respond to immunotherapy) in triple-negative breast cancer patients, the proportion of Clostridium spp.

With the help of multidimensional omics analysis, the study found that in the breast microenvironment of the immunomodulatory subtype ( Immunomodulatory, IM , the group that can respond to immunotherapy) in triple-negative breast cancer patients, the proportion of Clostridium spp.

Combined with metabolic data analysis, it was found that Clostridium-related metabolite TMAO was more abundant in patients with IM subtype, and was positively correlated with the proportion of CD8+ T cells and the expression of γ- interferon in the microenvironment .

Schematic diagram of bacterial flora promoting anti-tumor immunity through metabolite TMAO 

Schematic diagram of bacterial flora promoting anti-tumor immunity through metabolite TMAO 

Different from the anti-tumor activators reported in common articles that directly act on immune cells, this study from a unique perspective found that the special microbial community directly acts on tumor cells with the help of metabolites, inducing their pyroptosis, and then promoting immune cell infiltration.

Different from the anti-tumor activators reported in common articles that directly act on immune cells, this study from a unique perspective found that the special microbial community directly acts on tumor cells with the help of metabolites, inducing their pyroptosis, and then promoting immune cell infiltration.

The problem of the efficacy of triple-negative breast cancer immunotherapy needs to be solved urgently

" Breast cancer is like a ' big family ' and can be subdivided into four subtypes: luminal A , luminal B , HER-2 positive and triple negative, with triple negative breast cancer being the most ' toxic ' type, " the project Professor Shao Zhimin, the principal investigator, said, " Triple-negative breast cancer accounts for 10%-20% of the total breast cancer population , and its estrogen receptor, progesterone receptor and HER-2 expression are all negative .

" Breast cancer is like a ' big family ' and can be subdivided into four subtypes: luminal A , luminal B , HER-2 positive and triple negative, with triple negative breast cancer being the most ' toxic ' type, " the project Professor Shao Zhimin, the principal investigator, said, " Triple-negative breast cancer accounts for 10%-20% of the total breast cancer population , and its estrogen receptor, progesterone receptor and HER-2 expression are all negative .

In recent years, immunotherapy represented by PD-1 inhibitors has become a promising treatment for triple-negative breast cancer .

Unique Perspective Reveals New Strategy: Small Bacteria Become Key " Reinforcement " for Immunotherapy Unique Perspective Reveals New Strategy: Small Bacteria Becomes Key " Reinforcement " for Immunotherapy

In previous studies, scientists from various countries have studied immunotherapy from the perspective of the human body, trying to improve the efficacy of immunotherapy by regulating tumor cells and immune cells, but they often overlooked an important role - symbiotic bacteria

In previous studies, scientists from various countries have studied immunotherapy from the perspective of the human body, trying to improve the efficacy of immunotherapy by regulating tumor cells and immune cells, but they often overlooked an important role - symbiotic bacteria

A large number of bacteria live in the human body.

Such commensal flora is an important part of the cellular microenvironment, whether in normal breast tissue or breast tissue with breast cancer
.
So on the battlefield where tumor cells and immune cells are fighting, is the mysterious force of the symbiotic flora an " enemy " or a " friend " , and does it play a role in the fight against tumors?

In order to explore this scientific question, the team based on the triple-negative breast cancer cohort of Fudan University Affiliated Cancer Hospital, analyzed through multi-omics dimensions, and found that the proportion of Clostridium in the breast microenvironment of patients with immunomodulatory subtypes ( IM ) was significant.
higher than other subtypes, suggesting that intratumoral commensal microbiota may affect the tumor microenvironment of triple-negative breast cancer
.
Combined with metabolic data analysis, it was found that the Clostridium-related metabolite TMAO also has a higher abundance in patients with IM subtype, and is positively correlated with the proportion of CD8+ T cells in the microenvironment, and CD8+ T is the key to the anti-tumor function of the human body.
" Warrior " .
Therefore, the Clostridium commensal bacteria and related metabolites TMAO are the " friends " of the human body in the fight against triple-negative breast cancer .


 

In order to explore this scientific question, the team based on the triple-negative breast cancer cohort of Fudan University Affiliated Cancer Hospital, analyzed through multi-omics dimensions, and found that the proportion of Clostridium in the breast microenvironment of patients with immunomodulatory subtypes ( IM ) was significant.
higher than other subtypes, suggesting that intratumoral commensal microbiota may affect the tumor microenvironment of triple-negative breast cancer
.
Combined with metabolic data analysis, it was found that the Clostridium-related metabolite TMAO also has a higher abundance in patients with IM subtype, and is positively correlated with the proportion of CD8+ T cells in the microenvironment, and CD8+ T is the key to the anti-tumor function of the human body.
" Warrior " .
Therefore, the Clostridium commensal bacteria and related metabolites TMAO are the " friends " of the human body in the fight against triple-negative breast cancer .


 

The team further explored how TMAO helps the body suppress triple-negative breast cancer
.
The research team carried out related experiments based on mouse animal models and found that up-regulation of intratumoral TMAO levels can activate the function of CD8+ T cells and effectively inhibit the growth of triple-negative breast cancer by increasing the infiltration of CD8+ T cells in the intratumoral microenvironment .
Mechanistic exploration found that TMAO induces GSDME -mediated pyroptosis in breast cancer cells , releasing a large number of inflammatory factors into the microenvironment, thereby increasing the infiltration of CD8+ T cells in the microenvironment, and activating CD8+ T cells to play anti-tumor functions .
The study also found that TMAO -induced tumor cell pyroptosis is closely related to endoplasmic reticulum stress .
TMAO induces pyroptosis of tumor cells by activating PERK protein and further cleaving the upstream protein caspase-3 of GSMDE .




 

The team further explored how TMAO helps the body suppress triple-negative breast cancer
.
The research team carried out related experiments based on mouse animal models and found that up-regulation of intratumoral TMAO levels can activate the function of CD8+ T cells and effectively inhibit the growth of triple-negative breast cancer by increasing the infiltration of CD8+ T cells in the intratumoral microenvironment .
Mechanistic exploration found that TMAO induces GSDME -mediated pyroptosis in breast cancer cells , releasing a large number of inflammatory factors into the microenvironment, thereby increasing the infiltration of CD8+ T cells in the microenvironment, and activating CD8+ T cells to play anti-tumor functions .
The study also found that TMAO -induced tumor cell pyroptosis is closely related to endoplasmic reticulum stress .
TMAO induces pyroptosis of tumor cells by activating PERK protein and further cleaving the upstream protein caspase-3 of GSMDE .




 

Microbial metabolites are expected to boost immunotherapy in the future

Microbial metabolites are expected to boost immunotherapy in the future Microbial metabolites are expected to boost immunotherapy in the future

After discovering this exciting scientific phenomenon, the team is also actively advancing translational research
.
Combined with the clinical triple-negative breast cancer immunotherapy cohort, the research team found that patients with high plasma TMAO levels were more responsive to immunotherapy, and in vivo experiments in mice also confirmed that increasing plasma TMAO levels can effectively inhibit tumor growth in mice
.
 

After discovering this exciting scientific phenomenon, the team is also actively advancing translational research
.
Combined with the clinical triple-negative breast cancer immunotherapy cohort, the research team found that patients with high plasma TMAO levels were more responsive to immunotherapy, and in vivo experiments in mice also confirmed that increasing plasma TMAO levels can effectively inhibit tumor growth in mice
.
 

In order to explore a clinically feasible treatment plan, the research team increased plasma TMAO and intratumoral levels by feeding mice TMAO precursor metabolite choline , and confirmed that supplemental choline intake can activate anti-tumor immunity in triple-negative breast cancer and improve immunity therapeutic efficacy .
Choline is one of the nutrients ingested by the human body daily.
It is commonly found in protein, fish, and beef.
It is safe and is often used as a nutritional supplement in clinical practice in the past .
Therefore, supplemental choline intake is expected to be a potential clinical treatment strategy to improve the efficacy of immunotherapy for triple-negative breast cancer .
Professor Shao's team has also started a clinical trial of oral choline to improve the efficacy of triple-negative breast cancer immunotherapy, hoping to promote the development of triple-negative breast cancer immunotherapy .

In order to explore a clinically feasible treatment plan, the research team increased plasma TMAO and intratumoral levels by feeding mice TMAO precursor metabolite choline , and confirmed that supplemental choline intake can activate anti-tumor immunity in triple-negative breast cancer and improve immunity therapeutic efficacy .
Choline is one of the nutrients ingested by the human body daily.
It is commonly found in protein, fish, and beef.
It is safe and is often used as a nutritional supplement in clinical practice in the past .
Therefore, supplemental choline intake is expected to be a potential clinical treatment strategy to improve the efficacy of immunotherapy for triple-negative breast cancer .
Professor Shao's team has also started a clinical trial of oral choline to improve the efficacy of triple-negative breast cancer immunotherapy, hoping to promote the development of triple-negative breast cancer immunotherapy .

" Based on the ' Fudan typing ' , we focused on the clinical issues of immunotherapy from the unique perspective of the microbial metabolome and found that the microbial metabolite TMAO can activate anti-tumor immunity in triple-negative breast cancer and improve the efficacy of immunotherapy
.
" Professor Shao said, " This study further improves the system of " clinical issues - scientific research - clinical practice " in breast surgery of Fudan University Affiliated Cancer Hospital , and provides a new strategy for precise immunotherapy of triple-negative breast cancer
.
Improve the efficacy of immunotherapy in clinical practice and practically help triple-negative breast cancer patients
.
”  

" Based on the ' Fudan typing ' , we focused on the clinical issues of immunotherapy from the unique perspective of the microbial metabolome and found that the microbial metabolite TMAO can activate anti-tumor immunity in triple-negative breast cancer and improve the efficacy of immunotherapy
.
" Professor Shao said, " This study further improves the system of " clinical issues - scientific research - clinical practice " in breast surgery of Fudan University Affiliated Cancer Hospital , and provides a new strategy for precise immunotherapy of triple-negative breast cancer
.
Improve the efficacy of immunotherapy in clinical practice and practically help triple-negative breast cancer patients
.
”  

Wang Hai, Rong Xingyu, Zhao Gan and Zhou Yifan of Fudan University Cancer Hospital are the co-first authors of the paper, and Shao Zhimin, Zhao Chao and Jiang Yizhou are the co-corresponding authors
.

Wang Hai, Rong Xingyu, Zhao Gan and Zhou Yifan of Fudan University Cancer Hospital are the co-first authors of the paper, and Shao Zhimin, Zhao Chao and Jiang Yizhou are the co-corresponding authors
.

Paper link:

Paper link:

The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer.
Cell Metabolism.
2022.
https://doi.
org/10.
1016/j.
cmet.
2022.
02.
010

The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer.
Cell Metabolism.
2022.
https://doi.
org/10.
1016/j.
cmet.
2022.
02.
010

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