Recently, the team of Wang Likun, a researcher at the Institute of Biophysics, Chinese Academy of Sciences, discovered that tumor cells can hijack a transcription factor called XBP1 and produce cholesterol themselves when experiencing endoplasmic reticulum stress.
Cholesterol can be secreted out of cells in the form of small extracellular vesicles and taken up by a type of tumor-infiltrating immunosuppressive cells called bone marrow-derived suppressor cells, thereby suppressing anti-tumor immunity.
Picture | Wang Likun (Source: Wang Likun)
Through the above method, tumor cells can escape the attack of cytotoxic T cells , thereby promoting their own growth. Using small molecule inhibitors to prevent the production of XBP1 or reduce cholesterol levels can effectively slow down tumor growth.
Previously, many studies have used unfolded protein response as a potential target for tumor treatment. Some small molecule inhibitors or activators have also entered preclinical research, but there are no drugs that have actually entered clinical use.
The American company Amgen has reported that the screened small molecule inhibitor targeting IRE1α can inhibit the production of its downstream XBP1s, and said that in multiple natural tumor cell lines, it has not been found that inhibition of the IRE1α pathway can effectively prevent the growth of tumor cells.
"And this is consistent with the experimental results of our tumor cell culture in vitro. Interestingly, we found that tumor cell growth has a significant impact on XBP1s The dependence of immune function is only reflected in mice with normal . This also reminds us that we cannot ignore the existence of immune system in tumor research or screening of tumor drugs. Perhaps by adjusting this idea, people can gain new understanding and application of unfolded protein response as an anti-tumor target. " Wang Likun said.
(Source: Cell Metabolism)
It was first discovered that XBP1 directly upregulates the expression of cholesterol synthase
According to reports, Wang Likun’s research group has long been concerned about endoplasmic reticulum stress and unfolded protein response. endoplasmic reticulum is an important organelle in cells responsible for protein folding and transport, and lipid synthesis and transport.
However, for many cells, they will be interfered by internal and external factors, such as gene mutations, the synthesis of large amounts of secreted protein , hypoxia, pathogen invasion, etc. This will hinder the folding and transport of proteins, resulting in the accumulation of incorrectly folded protein in the endoplasmic reticulum lumen.
is like a protein "processing factory". There is a backlog of products due to poor product quality or overcapacity. In cells, this phenomenon is called "endoplasmic reticulum stress."
Of course, the "processing factory" will report this situation to its superiors, or tell other organelles , and everyone will work together to overcome the difficulties. This process is called the "unfolded protein response".
That is, when endoplasmic reticulum stress occurs, the endoplasmic reticulum notifies the cell nucleus through a series of signaling pathways , and then starts the expression of certain specific genes by producing more molecular chaperones that can help protein folding. and folding enzyme (increase the number of workers), expand the volume of the endoplasmic reticulum (cover the production workshop), degrade unfolded proteins (dispose of defective products in a timely manner) and other means to help the endoplasmic reticulum return to normal status as soon as possible, or reduce the protein translation rate to slow down the pressure on the endoplasmic reticulum (shut down for rectification).
Endoplasmic reticulum stress and the unfolded protein response are common in tumor cells and immune cells , and are important for the survival and activity of these cells.
For example, some studies have found that when tumor cells face an unfavorable living environment, they can use unfolded protein responses to resist endoplasmic reticulum stress caused by these adverse factors; immune cells secrete proteins such as antibodies and cytokines , which are also on the "front line" in resisting pathogenic invasion and clearing foreign matter. Therefore, if they want to function normally, they must also rely on unfolded protein responses.
However, little is known about how tumor cells use their own unfolded proteins to respond to signals to affect surrounding cells, especially immune cells.
(Source: Cell Metabolism)
This work found that: This response signal of tumor cells can affect immune cells across cells, thereby preventing immune cells from killing tumor cells. This also shows that in complex diseases such as tumors, endoplasmic reticulum stress signals can be transmitted between different cells.
According to reports, XBP1 is a very important transcription factor downstream of IRE1α, one of the unfolded protein response pathways, and is responsible for reporting endoplasmic reticulum stress signals to nucleus .
When endoplasmic reticulum stress occurs, activation of IRE1α can lead to specific splicing of XBP1 mRNA, which leads to the production of XBP1 protein with transcription factor activity. XBP1 then enters the nucleus and binds to certain specific gene fragments on DNA, thereby initiating their transcription of .
This study found that in tumor cells, XBP1 can directly bind to the promoter regions of genes transcribed by some enzymes involved in cholesterol synthesis. By upregulating the expression of these genes, the ability of tumor cells to synthesize cholesterol can be improved.
Wang Likun said: "There have been many reports before about the discovery that unfolded protein response can affect lipid synthesis. However, this is the first time we discovered that XBP1 directly upregulates the expression of cholesterol synthase."
(Source: Cell Metabolism)
Analysis of tumor-related clinical databases showed that XBP1 It is highly expressed in a variety of tumor tissues, which implies that it may be related to the occurrence and development of tumors. In the
study, the team transplanted the mouse melanoma cell line B16.F10 (hereinafter referred to as "B16") and colon cancer cell line (MC-38) into mice subcutaneously. When tested after tumor formation, the expression of XBP1 can indeed be observed. This shows that tumor cells have experienced endoplasmic reticulum stress and initiated an unfolded protein response.
However, in immunodeficient mice, the growth rate of tumor cells lacking XBP1 was not affected. Only when inoculated into mice with intact immune systems, the tumor formation rate was significantly slower than that of wild-type cells. This suggests that XBP1 in tumor cells can influence the immune system in some way, thereby promoting tumor growth.
In fact, tumor tissues are extremely complex and contain infiltration of different types of immune cells. At present, the tumor microenvironment, especially the mutual regulation of , tumor immunity and , has received widespread attention from the academic community. The recently popular tumor immunotherapy is based on the above theory.
Tumor cells can secrete a large number of functional molecules, which can affect immune cell activity. In turn, immune cells can also regulate tumor cells. Immune cells and tumor cells are also interacting with each other, like a "free-for-all", during which there are various "infighting" and "undercover disguises". The
research group also found that the deletion of XBP1 in tumor cells significantly reduced the proportion of myeloid-derived suppressor cells in tumor tissue, which was also accompanied by an increase in the proportion of CD8+ T cells.
In addition, the deletion of XBP1 also reduces the cholesterol content in tumor tissues, which is consistent with the previously mentioned XBP1 promoting the transcription of key genes for cholesterol synthesis. Recently, the team of Wang Likun, a researcher at the Institute of Biophysics, Chinese Academy of Sciences, discovered that
Cholesterol can be secreted out of cells in the form of small extracellular vesicles and taken up by a type of tumor-infiltrating immunosuppressive cells called bone marrow-derived suppressor cells, thereby suppressing anti-tumor immunity.
Picture | Wang Likun (Source: Wang Likun)
Through the above method, tumor cells can escape the attack of cytotoxic T cells , thereby promoting their own growth. Using small molecule inhibitors to prevent the production of XBP1 or reduce cholesterol levels can effectively slow down tumor growth.
Previously, many studies have used unfolded protein response as a potential target for tumor treatment. Some small molecule inhibitors or activators have also entered preclinical research, but there are no drugs that have actually entered clinical use.
The American company Amgen has reported that the screened small molecule inhibitor targeting IRE1α can inhibit the production of its downstream XBP1s, and said that in multiple natural tumor cell lines, it has not been found that inhibition of the IRE1α pathway can effectively prevent the growth of tumor cells.
"And this is consistent with the experimental results of our tumor cell culture in vitro. Interestingly, we found that tumor cell growth has a significant impact on XBP1s The dependence of immune function is only reflected in mice with normal . This also reminds us that we cannot ignore the existence of immune system in tumor research or screening of tumor drugs. Perhaps by adjusting this idea, people can gain new understanding and application of unfolded protein response as an anti-tumor target. " Wang Likun said.
(Source: Cell Metabolism)
It was first discovered that XBP1 directly upregulates the expression of cholesterol synthase
According to reports, Wang Likun’s research group has long been concerned about endoplasmic reticulum stress and unfolded protein response. endoplasmic reticulum is an important organelle in cells responsible for protein folding and transport, and lipid synthesis and transport.
However, for many cells, they will be interfered by internal and external factors, such as gene mutations, the synthesis of large amounts of secreted protein , hypoxia, pathogen invasion, etc. This will hinder the folding and transport of proteins, resulting in the accumulation of incorrectly folded protein in the endoplasmic reticulum lumen.
is like a protein "processing factory". There is a backlog of products due to poor product quality or overcapacity. In cells, this phenomenon is called "endoplasmic reticulum stress."
Of course, the "processing factory" will report this situation to its superiors, or tell other organelles , and everyone will work together to overcome the difficulties. This process is called the "unfolded protein response".
That is, when endoplasmic reticulum stress occurs, the endoplasmic reticulum notifies the cell nucleus through a series of signaling pathways , and then starts the expression of certain specific genes by producing more molecular chaperones that can help protein folding. and folding enzyme (increase the number of workers), expand the volume of the endoplasmic reticulum (cover the production workshop), degrade unfolded proteins (dispose of defective products in a timely manner) and other means to help the endoplasmic reticulum return to normal status as soon as possible, or reduce the protein translation rate to slow down the pressure on the endoplasmic reticulum (shut down for rectification).
Endoplasmic reticulum stress and the unfolded protein response are common in tumor cells and immune cells , and are important for the survival and activity of these cells.
For example, some studies have found that when tumor cells face an unfavorable living environment, they can use unfolded protein responses to resist endoplasmic reticulum stress caused by these adverse factors; immune cells secrete proteins such as antibodies and cytokines , which are also on the "front line" in resisting pathogenic invasion and clearing foreign matter. Therefore, if they want to function normally, they must also rely on unfolded protein responses.
However, little is known about how tumor cells use their own unfolded proteins to respond to signals to affect surrounding cells, especially immune cells.
(Source: Cell Metabolism)
This work found that: This response signal of tumor cells can affect immune cells across cells, thereby preventing immune cells from killing tumor cells. This also shows that in complex diseases such as tumors, endoplasmic reticulum stress signals can be transmitted between different cells.
According to reports, XBP1 is a very important transcription factor downstream of IRE1α, one of the unfolded protein response pathways, and is responsible for reporting endoplasmic reticulum stress signals to nucleus .
When endoplasmic reticulum stress occurs, activation of IRE1α can lead to specific splicing of XBP1 mRNA, which leads to the production of XBP1 protein with transcription factor activity. XBP1 then enters the nucleus and binds to certain specific gene fragments on DNA, thereby initiating their transcription of .
This study found that in tumor cells, XBP1 can directly bind to the promoter regions of genes transcribed by some enzymes involved in cholesterol synthesis. By upregulating the expression of these genes, the ability of tumor cells to synthesize cholesterol can be improved.
Wang Likun said: "There have been many reports before about the discovery that unfolded protein response can affect lipid synthesis. However, this is the first time we discovered that XBP1 directly upregulates the expression of cholesterol synthase."
(Source: Cell Metabolism)
Analysis of tumor-related clinical databases showed that XBP1 It is highly expressed in a variety of tumor tissues, which implies that it may be related to the occurrence and development of tumors. In the
study, the team transplanted the mouse melanoma cell line B16.F10 (hereinafter referred to as "B16") and colon cancer cell line (MC-38) into mice subcutaneously. When tested after tumor formation, the expression of XBP1 can indeed be observed. This shows that tumor cells have experienced endoplasmic reticulum stress and initiated an unfolded protein response.
However, in immunodeficient mice, the growth rate of tumor cells lacking XBP1 was not affected. Only when inoculated into mice with intact immune systems, the tumor formation rate was significantly slower than that of wild-type cells. This suggests that XBP1 in tumor cells can influence the immune system in some way, thereby promoting tumor growth.
In fact, tumor tissues are extremely complex and contain infiltration of different types of immune cells. At present, the tumor microenvironment, especially the mutual regulation of , tumor immunity and , has received widespread attention from the academic community. The recently popular tumor immunotherapy is based on the above theory.
Tumor cells can secrete a large number of functional molecules, which can affect immune cell activity. In turn, immune cells can also regulate tumor cells. Immune cells and tumor cells are also interacting with each other, like a "free-for-all", during which there are various "infighting" and "undercover disguises". The
research group also found that the deletion of XBP1 in tumor cells significantly reduced the proportion of myeloid-derived suppressor cells in tumor tissue, which was also accompanied by an increase in the proportion of CD8+ T cells.
In addition, the deletion of XBP1 also reduces the cholesterol content in tumor tissues, which is consistent with the previously mentioned XBP1 promoting the transcription of key genes for cholesterol synthesis.
Interestingly, both in vitro and in vivo experiments have confirmed the following rule: cholesterol plays an important role in the expansion and activation of bone marrow-derived suppressor cells. Since bone marrow-derived suppressor cells are a type of immunosuppressive cells, previous studies and this experimental data have shown that they can inhibit the activity of CD8+T cells, and CD8+T cells can kill tumor cells.
For example, tumor cells take advantage of the endoplasmic reticulum protein "processing factory" to "appropriate" the unfolded protein response signal molecule XBP1 to produce cholesterol, and these cholesterol can also be "exported" to bone marrow-derived suppressor cells. The number and activity of bone marrow-derived suppressor cells that "eat well and drink well" have increased, so a fierce counterattack has been launched against the attack of CD8+ T cells on tumor cells.
In this way, by upregulating cholesterol synthesis, cholesterol secretion can be increased. At this time, tumor cells can achieve the purpose of suppressing anti-tumor immunity and paving the way for self-growth.
But how is cholesterol from tumor cells “exported” to myeloid-derived suppressor cells? This must mention a type of single-membrane structure vesicles called small extracellular vesicles.
In recent years, studies have found that small extracellular vesicles play an important role in intercellular material transfer. In addition, there are many studies on how tumor cells secrete microRNA or proteins through small extracellular vesicles to affect the surrounding environment.
According to reports, small extracellular vesicles are also carriers of cholesterol. This study found that XBP1 deletion reduced cholesterol secretion in tumor cells by reducing the cholesterol content on small extracellular vesicles.
In this way, hydrophobic cholesterol molecules are able to cross the "ocean" of the hydrophilic environment between cells and come to the side of the bone marrow-derived suppressor cells.
The bone marrow-derived suppressor cells take up cholesterol molecules through a method called "macropinocytosis", and then expand and activate.
If the production of small extracellular vesicles in tumor cells is prevented by treating the inhibitor or knocking out via the gene, tumor growth will be inhibited. In tumor tissue, the proportions of bone marrow-derived suppressor cells and CD8+ T cells will also decrease and increase respectively.
This shows that in addition to transporting RNA and proteins, small extracellular vesicles can also serve as carriers of cholesterol and play a role in signaling between cells.
Since the XBP1 signaling pathway can inhibit anti-tumor immunity by upregulating the synthesis and secretion of cholesterol. So, can injection of inhibitors of this signaling pathway also inhibit tumor growth in mice inoculated with tumor cells?
experimental results show that in the unfolded protein upstream of XBP1, the inhibitor KIRA8 of the responsive protein IRE1α can indeed slow down the growth of tumors, which is also accompanied by a decrease in cholesterol content in tumor tissue, a decrease in the number of bone marrow-derived suppressor cells, and an increase in the number of CD8+ T cells.
This also means that on mouse models, the team confirmed the impact of this pathway on tumors. Not only that, KIRA8 can show better results in melanoma models when combined with the currently popular immune checkpoint inhibitor-PD-1 antibody.
You must know that some tumors are not sensitive to immunotherapy, and KIRA8 can be used to re-mobilize the enthusiasm of the immune system and combined with PD-1 antibodies may help treat these tumors.
It is worth mentioning that KIRA8 is an IRE1α inhibitor first reported by the American company Amgen. In vitro experiments have shown that IRE1α inhibitors have no significant effect on killing tumor cells. However, this does not take into account the impact of the immune system.
In this study, the research team considered the impact of the immune system on tumors, and the effect of KIRA8 was also shown. It was also confirmed that if B16 melanoma cells were inoculated into immunodeficient mice, KIRA8 would indeed not produce an anti-tumor effect.
Recently, a related paper titled "Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production" was published on Cell Metabolism (IF 31.37), Zaili Yang is the first author, and Wang Likun serves as the corresponding author [1].
Figure | Related papers (Source: Cell Metabolism)
It can be said that although many studies have revealed that bone marrow-derived suppressor cells can promote tumors, and that XBP1s can promote multiple mechanisms in the malignant progression of tumors, this work found that tumor cells XBP1s Directly regulating the expression of genes related to cholesterol biosynthesis, and using extracellular vesicles to "remotely regulate" anti-tumor immunity, these new experimental data have also improved people's understanding.
"As long as you take the problem seriously, others will also help you seriously"
Originally, in the early stages of the research, the team just wanted to better understand the unfolded protein response and its regulatory role in cell-to-cell signal communication.
Tumor tissue contains a variety of different cells, including tumor cells and immune cells, and is a very typical research model. Therefore, they first explored the impact of the IRE1α/XBP1 signaling pathway in tumor cells on immune cells within tumors.
Since the laboratory has no foundation in tumor immunity, the process was quite difficult. "Fortunately, the Institute of Biophysics has very outstanding tumor immunology scientists who have given great help, especially the laboratory of Teacher Yang Pengyuan and the laboratory of Teacher Fu Yangxin /Peng Hua." Wang Likun said.
After repeated exploration, and through mass spectrometry flow cytometry and flow cytometry analysis, they finally determined that XBP1 of tumor cells can affect the number and function of myeloid-derived suppressor cells in the tumor microenvironment. After
, the research team began to find out which factors regulated by XBP1 would act on bone marrow-derived suppressor cells. At first, limited by their inherent thinking, they wanted to find some new cytokines that could stimulate the expansion and activation of bone marrow-derived suppressor cells, but they ended in failure.
Subsequently, combined with transcriptome sequencing analysis and in vitro experimental verification, the research team finally found cholesterol regulated by XBP1, which can stimulate the activation and expansion of bone marrow-derived suppressor cells.
In the process of searching for a carrier to deliver cholesterol, Zhou Shixin, a doctoral student in Wang Likun's laboratory, provided a lot of help. He has rich experience in the direction of exosomes. At this stage, they established the theory that exosomes are important carriers of cholesterol from tumor cells to bone marrow-derived suppressor cells.
Subsequently, the research team explored the mechanism by which bone marrow-derived suppressor cells receive cholesterol. "Among them, Professor Cai Huaqing, who is mainly engaged in research on cell movement and pinocytosis mechanisms, gave very good guidance. In the end, we clarified that bone marrow-derived suppressor cells receive cholesterol delivered from tumor cells mainly through macropinocytosis." Wang Likun said.
Finally, after clarifying the mechanism by which the XBP1 signaling pathway regulates tumor immunity, it was discovered that blocking XBP1 signaling with small molecule compounds can effectively inhibit tumor growth. As mentioned before, its combination with the marketed tumor immunotherapy drug PD-1 antibody can more effectively limit tumor growth.
In fact, the research team did not think about the detail that cholesterol is a key molecule in signal transmission between tumor cells and bone marrow-derived suppressor cells at first, and took it for granted that it should be a protein-based cytokine. Of course, this is also reasonable, after all, cytokines play an important role in tumor immunity.
However, after a series of experiments, the results were always specious, and the progress of scientific research was also slowed down.Then they thought, what if it’s not protein? So I started to think about lipids, because in addition to being closely related to protein transport, the endoplasmic reticulum also plays an important role in lipid synthesis and transport.
Wang Likun said: "We also discussed this several times with teacher Liu Pingsheng in the institute. Later, through omics analysis and combined with in vitro experiments, we gradually clarified the key role of cholesterol in it. During this period, we analyzed many tumors and h Teachers on tml1 immunity and lipid metabolism asked many questions, and they all generously provided help. This free and harmonious academic atmosphere is also a necessary condition for smooth work. "
(Source: Cell. Metabolism)
The submission process also made Wang Likun quite emotional. The research team had no previous research experience in tumor immunity, and this was the first independently published paper after the establishment of the laboratory.
He said: "There is a saying that the editors of top magazines will look at your research background. If you are a novice in this field, they will naturally review the paper with a more demanding attitude. However, the entire review process gives us the feeling that both the editor and the anonymous reviewers are very objective in their evaluation and suggestions."
In the first round of review, there was a reviewer who obviously had an immunology background. Most of the 20 questions were very difficult, and the other party bluntly pointed out in the comments that there were many loopholes in immunology in this work.
Later, the team spent 5 months supplementing the paper and found that solving these problems was very helpful in improving the quality of the paper. After returning the revised draft in response to the review comments, the reviewer's attitude changed significantly.
"I think no matter whether you are a novice or not, as long as you take the problem seriously and have the courage to admit your shortcomings, others will be serious about helping you." Wang Likun said.
In the follow-up, the research team plans to further explore how cholesterol affects bone marrow-derived suppressor cells. At present, one possibility is that cholesterol also causes endoplasmic reticulum stress on bone marrow-derived suppressor cells, which has also been reported in related studies of T cells.
However, it is also possible that cholesterol changes the structure of cell membrane , resulting in changes in the activity of some membrane localization signal molecules. Of course, cholesterol may also be involved in cellular metabolism, and these are interesting questions.
In addition, there is currently varying understanding of the role of cholesterol in anti-tumor immunity. This study and other studies show that cholesterol has the function of inhibiting anti-tumor immunity, but some studies have also found that it can promote anti-tumor immunity, which is also a reflection of the complexity of tumor immunity. So, will the high-cholesterol diet increase or decrease the risk of cancer? This will be the "next stop" of Wang Likun's research.
Reference:
. Yang, Z., Huo, Y., Zhou, S., Guo, J., Ma, X., Li, T., ... & Wang, L. (2022). Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.Cell Metabolism, 34(12), 2018-2035.
Recently, a related paper titled "Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production" was published on Cell Metabolism (IF 31.37), Zaili Yang is the first author, and Wang Likun serves as the corresponding author [1].
Figure | Related papers (Source: Cell Metabolism)
It can be said that although many studies have revealed that bone marrow-derived suppressor cells can promote tumors, and that XBP1s can promote multiple mechanisms in the malignant progression of tumors, this work found that tumor cells XBP1s Directly regulating the expression of genes related to cholesterol biosynthesis, and using extracellular vesicles to "remotely regulate" anti-tumor immunity, these new experimental data have also improved people's understanding.
"As long as you take the problem seriously, others will also help you seriously"
Originally, in the early stages of the research, the team just wanted to better understand the unfolded protein response and its regulatory role in cell-to-cell signal communication.
Tumor tissue contains a variety of different cells, including tumor cells and immune cells, and is a very typical research model. Therefore, they first explored the impact of the IRE1α/XBP1 signaling pathway in tumor cells on immune cells within tumors.
Since the laboratory has no foundation in tumor immunity, the process was quite difficult. "Fortunately, the Institute of Biophysics has very outstanding tumor immunology scientists who have given great help, especially the laboratory of Teacher Yang Pengyuan and the laboratory of Teacher Fu Yangxin /Peng Hua." Wang Likun said.
After repeated exploration, and through mass spectrometry flow cytometry and flow cytometry analysis, they finally determined that XBP1 of tumor cells can affect the number and function of myeloid-derived suppressor cells in the tumor microenvironment. After
, the research team began to find out which factors regulated by XBP1 would act on bone marrow-derived suppressor cells. At first, limited by their inherent thinking, they wanted to find some new cytokines that could stimulate the expansion and activation of bone marrow-derived suppressor cells, but they ended in failure.
Subsequently, combined with transcriptome sequencing analysis and in vitro experimental verification, the research team finally found cholesterol regulated by XBP1, which can stimulate the activation and expansion of bone marrow-derived suppressor cells.
In the process of searching for a carrier to deliver cholesterol, Zhou Shixin, a doctoral student in Wang Likun's laboratory, provided a lot of help. He has rich experience in the direction of exosomes. At this stage, they established the theory that exosomes are important carriers of cholesterol from tumor cells to bone marrow-derived suppressor cells.
Subsequently, the research team explored the mechanism by which bone marrow-derived suppressor cells receive cholesterol. "Among them, Professor Cai Huaqing, who is mainly engaged in research on cell movement and pinocytosis mechanisms, gave very good guidance. In the end, we clarified that bone marrow-derived suppressor cells receive cholesterol delivered from tumor cells mainly through macropinocytosis." Wang Likun said.
Finally, after clarifying the mechanism by which the XBP1 signaling pathway regulates tumor immunity, it was discovered that blocking XBP1 signaling with small molecule compounds can effectively inhibit tumor growth. As mentioned before, its combination with the marketed tumor immunotherapy drug PD-1 antibody can more effectively limit tumor growth.
In fact, the research team did not think about the detail that cholesterol is a key molecule in signal transmission between tumor cells and bone marrow-derived suppressor cells at first, and took it for granted that it should be a protein-based cytokine. Of course, this is also reasonable, after all, cytokines play an important role in tumor immunity.
However, after a series of experiments, the results were always specious, and the progress of scientific research was also slowed down.Then they thought, what if it’s not protein? So I started to think about lipids, because in addition to being closely related to protein transport, the endoplasmic reticulum also plays an important role in lipid synthesis and transport.
Wang Likun said: "We also discussed this several times with teacher Liu Pingsheng in the institute. Later, through omics analysis and combined with in vitro experiments, we gradually clarified the key role of cholesterol in it. During this period, we analyzed many tumors and h Teachers on tml1 immunity and lipid metabolism asked many questions, and they all generously provided help. This free and harmonious academic atmosphere is also a necessary condition for smooth work. "
(Source: Cell. Metabolism)
The submission process also made Wang Likun quite emotional. The research team had no previous research experience in tumor immunity, and this was the first independently published paper after the establishment of the laboratory.
He said: "There is a saying that the editors of top magazines will look at your research background. If you are a novice in this field, they will naturally review the paper with a more demanding attitude. However, the entire review process gives us the feeling that both the editor and the anonymous reviewers are very objective in their evaluation and suggestions."
In the first round of review, there was a reviewer who obviously had an immunology background. Most of the 20 questions were very difficult, and the other party bluntly pointed out in the comments that there were many loopholes in immunology in this work.
Later, the team spent 5 months supplementing the paper and found that solving these problems was very helpful in improving the quality of the paper. After returning the revised draft in response to the review comments, the reviewer's attitude changed significantly.
"I think no matter whether you are a novice or not, as long as you take the problem seriously and have the courage to admit your shortcomings, others will be serious about helping you." Wang Likun said.
In the follow-up, the research team plans to further explore how cholesterol affects bone marrow-derived suppressor cells. At present, one possibility is that cholesterol also causes endoplasmic reticulum stress on bone marrow-derived suppressor cells, which has also been reported in related studies of T cells.
However, it is also possible that cholesterol changes the structure of cell membrane , resulting in changes in the activity of some membrane localization signal molecules. Of course, cholesterol may also be involved in cellular metabolism, and these are interesting questions.
In addition, there is currently varying understanding of the role of cholesterol in anti-tumor immunity. This study and other studies show that cholesterol has the function of inhibiting anti-tumor immunity, but some studies have also found that it can promote anti-tumor immunity, which is also a reflection of the complexity of tumor immunity. So, will the high-cholesterol diet increase or decrease the risk of cancer? This will be the "next stop" of Wang Likun's research.
Reference:
. Yang, Z., Huo, Y., Zhou, S., Guo, J., Ma, X., Li, T., ... & Wang, L. (2022). Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.Cell Metabolism, 34(12), 2018-2035.
