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*For medical professionals only, SIBCS highlights and should not be missed!
Breast cancer classification is complex, among which triple-negative breast cancer (TNBC) is known as the "king of breast cancer" due to its extremely poor prognosis
.
In recent years, the development of immunotherapy has brought certain breakthroughs
to the treatment of TNBC.
How to improve the effect of immunotherapy and overcome this stubborn and intractable "fortress"? The team of Professor Shao Zhimin of Fudan University Cancer Hospital has carried out a series of key research on TNCB and achieved fruitful results
.
Recently, the 17th National Breast Cancer Conference (CBCC) and the 17th Shanghai International Breast Cancer Forum (SIBCS) were successfully concluded
.
At the meeting, Professor Shao Zhimin gave a speech entitled "Dancing with Bacteria: When Oncology Meets Microbiology", introducing his team's new achievements
in the field of TNBC to the audience.
The medical profession has specially extracted the essence for readers
.
Three years of research, precision treatment strategy has been a great success Professor Shao Zhimin introduced that TNBC has the three characteristics of rapid disease progression, easy early recurrence and metastasis, and lack of therapeutic targets, in order to overcome this difficulty, Professor Shao Zhimin's team has carried out a number of studies on the treatment of TNBC, drawn a multi-omics map of TNBC, and summarized the "Fudan classification".
Propose precision treatment strategies
.
His team found that immunomodulatory (IM) subtypes are a potential beneficiary of immune checkpoint inhibitors
.
Under the guidance of "Fudan typing", the TNBC immunotherapy clinical trial - FUTURE study has obtained gratifying results
.
The study included patients with advanced triple-negative breast cancer who did not respond to multiple lines and gave different treatment regimens for different types, with the primary endpoint being objective response rate (ORR).
The results showed an ORR of 29% of the overall intention-to-treat population (ITT), with an ORR of 52.
6%
in the immunotherapy group (C-arm, a combination regimen of ABX+ immune checkpoint inhibitors administered to IM-typed patients).
On this basis, Professor Shao Zhimin's team further carried out the FUTURE-C-Plus trial to evaluate the efficacy
of the combination of immune checkpoint inhibitor + angiogenesis inhibitor + chemotherapy in TNBC patients with IM subtype.
Among the 48 participants, the ORR was as high as 81.
3% and the median progression-free survival (FPS) was 13.
6 months
.
The precision treatment strategy guided by "Fudan typing" has been initially successful in clinical trials, but Professor Shao Zhimin also pointed out that summarizing the current TNBC immunotherapy clinical trials can find that the results of different trials are heterogeneous, suggesting that there are still many problems to be solved
in this field.
In the era of precision medicine, how to improve the efficacy of TNBC immunotherapy? Professor Shao Zhimin proposed three key clinical problems and their solutions: (1) limited effective population for treatment:
analysis of breast cancer microenvironment characteristics to identify sensitive populations and key immune molecules;
(2) Low efficacy of monotherapy: explore the mechanism of immune escape and find precise combined immunity strategies;
(3) Insufficient clinical transformation of basic research: carry out immunotherapy clinical trials to promote the clinical transformation of
new targets.
Professor Shao Zhimin emphasized that the core of improving the efficacy of tumor immunotherapy is the key factor
affecting tumor and microenvironment.
Tumors and microenvironments are not only influenced by host factors, but also regulated
by their symbiotic flora.
There are a variety of commensal microbiota in tumor patients, and the abundance and composition of symbiotic microbiota are also different
depending on tumor types.
Harmful flora can play a cancer-promoting effect, while probiotics can play a cancer-suppressing function
.
Effects
of symbiotic microbiota on tumors and their microenvironment Professor Fang Jingyuan's team from the Department of Gastroenterology, Renji Hospital affiliated to Shanghai Jiao Tong University, revealed in 2017 that Fusobacterium nucleatum activates the autophagy pathway of tumor cells and promotes colorectal chemotherapy resistance by binding to TLR4 receptors, and follow-up studies further show that Fusobacterium nucleatum is a key pathogenic factor, biomarker and prevention target for colorectal cancer
.
Studies from the National Cancer Institute of the United States have shown that probiotics in tumors can activate the STING-IFNα/β pathway, activate anti-tumor immunity, and inhibit a variety of tumor progression
.
A high-fiber diet can increase probiotic content and improve sensitivity to immunotherapy
.
Breast cancer is also rich in commensal flora, which is significantly more abundant and diverse than tumors of other histological categories, as well as normal breast and paracancerous tissue
.
Therefore, it is of great significance
to study the symbiotic microbiota of breast cancer.
In 2022, Cai Shang's team at Westlake University reported that tumor intracellular bacteria in breast cancer can help tumor cells resist the pressure of fluid flow in blood vessels by remodeling the cytoskeleton and promoting breast cancer metastasis
.
The study is the first to confirm through direct experimental evidence that unique intracellular bacteria in breast cancer tissues play a key role
in tumor metastasis colonization.
Can intratumoral commensal flora regulate TNBC tumor immunity? Can targeting commensal microbiota improve immunotherapy efficacy? Based on this thinking, Professor Shao Zhimin's team conducted the FUSCC-TNBC clinical cohort study
.
The results showed that the symbiotic microbiota was an important part of the TNBC microenvironment, and there were individual differences
in the abundance of tumor symbiotic microbiota in different patients.
Clostridium genus is enriched in "hot tumors" (IM subtype), and the high abundance of Clostridium genus suggests a better
prognosis.
Fig.
1 Differences
in the abundance of tumor cobiotic flora in patients with TNBC of different subtypes Fig.
2 The high abundance of Clostridium stella suggests that the prognosis of TNBC patients has a better
metabolome analysis, and the clostridial metabolite trimethylamine oxide (TMAO) is positively correlated with immune activation.
Transcriptome analysis showed that TMAO was positively correlated
with signaling pathways for tumor immune activation.
These results suggest that commensal bacteria play an important role
in tumor immunity.
Fig.
3 Both metabolomic analysis and transcriptome analysis showed that choline in food, which plays an important role
in tumor immunity in TNBC patients, can be catalyzed by clostridial metabolic enzymes and human metabolic enzymes, and finally synthesized TMAO
.
Does TMAO produced by TNBC flora affect the microenvironment? Animal experiments gave a positive answer
.
Tumor microenvironment analysis showed that TMAO increased the infiltration of CD8+ T cells and enhanced the body's anti-tumor immune function
.
On this basis, the researchers further explored what downstream pathways TMAO used to affect the microenvironment of TNBC, and found that after TMAO treatment, TNBC cells underwent morphological and functional changes
of pyrosis.
After knocking down the key gene Gsdme of cell pyrosis, it is difficult for TMAO to inhibit tumor growth and activate anti-tumor immunity
in mice.
Therefore, the researchers concluded that TMAO can enhance anti-tumor immunity
by inducing pyroptosis in tumor cells.
Fig.
4 After knocking down the key gene Gsdme of cell pyrosis, TMAO is difficult to inhibit tumor growth and activate mouse anti-tumor immune pyrosis, which is a kind of programmed death mediated by the Gsdermin family, which is typically characterized by cell breakdown and mediated immune
activation
。 In vivo and in vitro tests have shown that TMAO activates PERK-mediated endoplasmic reticulum stress and its downstream elF2α-CHOP-ATF4 pathway, induces cell pyrosis, and then activates anti-tumor immunity
.
Fig.
5 TMAO activated PERK-mediated endoplasmic reticulum stress and its downstream elF2α-CHOP-ATF4 pathway, inducing cell pyrosis
, and the researchers also measured the concentration of TMAO in blood samples in the FUTURE study, and found that high TMAO concentration suggested better immunotherapy efficacy
in TNBC patients.
It is suggested that TMAO can be used as a biological marker for immunotherapy, and further elucidated the clinical value
of TMAO.
Fig.
6 Detection of TMAO concentration in blood samples in FUTURE study showed that high TMAO concentration suggested that TNBC patients received better
efficacy of immunotherapyIn addition, animal experiments have shown that choline supplementation can increase TMAO levels in mice, and oral choline can activate TNBC antitumor immunity and improve the efficacy of
PD-1 antibody immunotherapy 。 Based on the previous results, Professor Shao Zhimin's team initiated an exploratory phase II study, the Renaissance clinical trial
.
The study included patients with advanced TNBC who had progressed after immunotherapy and received choline combination immunotherapy with the aim of reversing immunotherapy resistance
.
Professor Shao Zhimin proudly pointed out that the research has three major innovations: conceptual innovation:
targeting TMAO, a key metabolite of commensal flora, and sensitizing TNBC immunotherapy
.
Mechanism breakthrough: TMAO induces cell pyrocytosis and activates anti-tumor immunity
by increasing endoplasmic reticulum stress.
Clinical translation: the use of choline-rich diet, increase TMAO in vivo, or can sensitize TNBC immunotherapy
.
The study was published in Cell Metabolism (IF=31.
7), a top international journal of metabolism, in the form of a cover article, and a review by Professor Yibin Kang of Princeton University, president of the International Society for Cancer Metastasis, was also published at the same time, saying that "this study has promoted the development of the field of tumor immunity and is expected to become an 'icebreaker' for immunotherapy"
.
Since 2019, Professor Shao Zhimin's team has published a number of representative and important papers on the topic of TNBC, initially forming a closed-loop research system
of "clinical-basic-clinical".
These research results have also been highly recognized by international peers and selected as the annual progress of the 2019/2021 International Breast Cancer Annual Conference, and Professor Shao Zhimin was invited to attend the keynote speech
of the 2021 International Breast Cancer Annual Conference.
They have made outstanding contributions to overcoming the difficult battle of the "king of breast cancer", and the results of these basic scientific research and clinical research have also provided guidance for the optimization of TNBC treatment strategies and brought new hope
to TNBC patients.
Breast cancer classification is complex, among which triple-negative breast cancer (TNBC) is known as the "king of breast cancer" due to its extremely poor prognosis
.
In recent years, the development of immunotherapy has brought certain breakthroughs
to the treatment of TNBC.
How to improve the effect of immunotherapy and overcome this stubborn and intractable "fortress"? The team of Professor Shao Zhimin of Fudan University Cancer Hospital has carried out a series of key research on TNCB and achieved fruitful results
.
Recently, the 17th National Breast Cancer Conference (CBCC) and the 17th Shanghai International Breast Cancer Forum (SIBCS) were successfully concluded
.
At the meeting, Professor Shao Zhimin gave a speech entitled "Dancing with Bacteria: When Oncology Meets Microbiology", introducing his team's new achievements
in the field of TNBC to the audience.
The medical profession has specially extracted the essence for readers
.
Three years of research, precision treatment strategy has been a great success Professor Shao Zhimin introduced that TNBC has the three characteristics of rapid disease progression, easy early recurrence and metastasis, and lack of therapeutic targets, in order to overcome this difficulty, Professor Shao Zhimin's team has carried out a number of studies on the treatment of TNBC, drawn a multi-omics map of TNBC, and summarized the "Fudan classification".
Propose precision treatment strategies
.
His team found that immunomodulatory (IM) subtypes are a potential beneficiary of immune checkpoint inhibitors
.
Under the guidance of "Fudan typing", the TNBC immunotherapy clinical trial - FUTURE study has obtained gratifying results
.
The study included patients with advanced triple-negative breast cancer who did not respond to multiple lines and gave different treatment regimens for different types, with the primary endpoint being objective response rate (ORR).
The results showed an ORR of 29% of the overall intention-to-treat population (ITT), with an ORR of 52.
6%
in the immunotherapy group (C-arm, a combination regimen of ABX+ immune checkpoint inhibitors administered to IM-typed patients).
On this basis, Professor Shao Zhimin's team further carried out the FUTURE-C-Plus trial to evaluate the efficacy
of the combination of immune checkpoint inhibitor + angiogenesis inhibitor + chemotherapy in TNBC patients with IM subtype.
Among the 48 participants, the ORR was as high as 81.
3% and the median progression-free survival (FPS) was 13.
6 months
.
The precision treatment strategy guided by "Fudan typing" has been initially successful in clinical trials, but Professor Shao Zhimin also pointed out that summarizing the current TNBC immunotherapy clinical trials can find that the results of different trials are heterogeneous, suggesting that there are still many problems to be solved
in this field.
In the era of precision medicine, how to improve the efficacy of TNBC immunotherapy? Professor Shao Zhimin proposed three key clinical problems and their solutions: (1) limited effective population for treatment:
analysis of breast cancer microenvironment characteristics to identify sensitive populations and key immune molecules;
(2) Low efficacy of monotherapy: explore the mechanism of immune escape and find precise combined immunity strategies;
(3) Insufficient clinical transformation of basic research: carry out immunotherapy clinical trials to promote the clinical transformation of
new targets.
Professor Shao Zhimin emphasized that the core of improving the efficacy of tumor immunotherapy is the key factor
affecting tumor and microenvironment.
Tumors and microenvironments are not only influenced by host factors, but also regulated
by their symbiotic flora.
There are a variety of commensal microbiota in tumor patients, and the abundance and composition of symbiotic microbiota are also different
depending on tumor types.
Harmful flora can play a cancer-promoting effect, while probiotics can play a cancer-suppressing function
.
Effects
of symbiotic microbiota on tumors and their microenvironment Professor Fang Jingyuan's team from the Department of Gastroenterology, Renji Hospital affiliated to Shanghai Jiao Tong University, revealed in 2017 that Fusobacterium nucleatum activates the autophagy pathway of tumor cells and promotes colorectal chemotherapy resistance by binding to TLR4 receptors, and follow-up studies further show that Fusobacterium nucleatum is a key pathogenic factor, biomarker and prevention target for colorectal cancer
.
Studies from the National Cancer Institute of the United States have shown that probiotics in tumors can activate the STING-IFNα/β pathway, activate anti-tumor immunity, and inhibit a variety of tumor progression
.
A high-fiber diet can increase probiotic content and improve sensitivity to immunotherapy
.
Breast cancer is also rich in commensal flora, which is significantly more abundant and diverse than tumors of other histological categories, as well as normal breast and paracancerous tissue
.
Therefore, it is of great significance
to study the symbiotic microbiota of breast cancer.
In 2022, Cai Shang's team at Westlake University reported that tumor intracellular bacteria in breast cancer can help tumor cells resist the pressure of fluid flow in blood vessels by remodeling the cytoskeleton and promoting breast cancer metastasis
.
The study is the first to confirm through direct experimental evidence that unique intracellular bacteria in breast cancer tissues play a key role
in tumor metastasis colonization.
Can intratumoral commensal flora regulate TNBC tumor immunity? Can targeting commensal microbiota improve immunotherapy efficacy? Based on this thinking, Professor Shao Zhimin's team conducted the FUSCC-TNBC clinical cohort study
.
The results showed that the symbiotic microbiota was an important part of the TNBC microenvironment, and there were individual differences
in the abundance of tumor symbiotic microbiota in different patients.
Clostridium genus is enriched in "hot tumors" (IM subtype), and the high abundance of Clostridium genus suggests a better
prognosis.
Fig.
1 Differences
in the abundance of tumor cobiotic flora in patients with TNBC of different subtypes Fig.
2 The high abundance of Clostridium stella suggests that the prognosis of TNBC patients has a better
metabolome analysis, and the clostridial metabolite trimethylamine oxide (TMAO) is positively correlated with immune activation.
Transcriptome analysis showed that TMAO was positively correlated
with signaling pathways for tumor immune activation.
These results suggest that commensal bacteria play an important role
in tumor immunity.
Fig.
3 Both metabolomic analysis and transcriptome analysis showed that choline in food, which plays an important role
in tumor immunity in TNBC patients, can be catalyzed by clostridial metabolic enzymes and human metabolic enzymes, and finally synthesized TMAO
.
Does TMAO produced by TNBC flora affect the microenvironment? Animal experiments gave a positive answer
.
Tumor microenvironment analysis showed that TMAO increased the infiltration of CD8+ T cells and enhanced the body's anti-tumor immune function
.
On this basis, the researchers further explored what downstream pathways TMAO used to affect the microenvironment of TNBC, and found that after TMAO treatment, TNBC cells underwent morphological and functional changes
of pyrosis.
After knocking down the key gene Gsdme of cell pyrosis, it is difficult for TMAO to inhibit tumor growth and activate anti-tumor immunity
in mice.
Therefore, the researchers concluded that TMAO can enhance anti-tumor immunity
by inducing pyroptosis in tumor cells.
Fig.
4 After knocking down the key gene Gsdme of cell pyrosis, TMAO is difficult to inhibit tumor growth and activate mouse anti-tumor immune pyrosis, which is a kind of programmed death mediated by the Gsdermin family, which is typically characterized by cell breakdown and mediated immune
activation
。 In vivo and in vitro tests have shown that TMAO activates PERK-mediated endoplasmic reticulum stress and its downstream elF2α-CHOP-ATF4 pathway, induces cell pyrosis, and then activates anti-tumor immunity
.
Fig.
5 TMAO activated PERK-mediated endoplasmic reticulum stress and its downstream elF2α-CHOP-ATF4 pathway, inducing cell pyrosis
, and the researchers also measured the concentration of TMAO in blood samples in the FUTURE study, and found that high TMAO concentration suggested better immunotherapy efficacy
in TNBC patients.
It is suggested that TMAO can be used as a biological marker for immunotherapy, and further elucidated the clinical value
of TMAO.
Fig.
6 Detection of TMAO concentration in blood samples in FUTURE study showed that high TMAO concentration suggested that TNBC patients received better
efficacy of immunotherapyIn addition, animal experiments have shown that choline supplementation can increase TMAO levels in mice, and oral choline can activate TNBC antitumor immunity and improve the efficacy of
PD-1 antibody immunotherapy 。 Based on the previous results, Professor Shao Zhimin's team initiated an exploratory phase II study, the Renaissance clinical trial
.
The study included patients with advanced TNBC who had progressed after immunotherapy and received choline combination immunotherapy with the aim of reversing immunotherapy resistance
.
Professor Shao Zhimin proudly pointed out that the research has three major innovations: conceptual innovation:
targeting TMAO, a key metabolite of commensal flora, and sensitizing TNBC immunotherapy
.
Mechanism breakthrough: TMAO induces cell pyrocytosis and activates anti-tumor immunity
by increasing endoplasmic reticulum stress.
Clinical translation: the use of choline-rich diet, increase TMAO in vivo, or can sensitize TNBC immunotherapy
.
The study was published in Cell Metabolism (IF=31.
7), a top international journal of metabolism, in the form of a cover article, and a review by Professor Yibin Kang of Princeton University, president of the International Society for Cancer Metastasis, was also published at the same time, saying that "this study has promoted the development of the field of tumor immunity and is expected to become an 'icebreaker' for immunotherapy"
.
Since 2019, Professor Shao Zhimin's team has published a number of representative and important papers on the topic of TNBC, initially forming a closed-loop research system
of "clinical-basic-clinical".
These research results have also been highly recognized by international peers and selected as the annual progress of the 2019/2021 International Breast Cancer Annual Conference, and Professor Shao Zhimin was invited to attend the keynote speech
of the 2021 International Breast Cancer Annual Conference.
They have made outstanding contributions to overcoming the difficult battle of the "king of breast cancer", and the results of these basic scientific research and clinical research have also provided guidance for the optimization of TNBC treatment strategies and brought new hope
to TNBC patients.
