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Yaoshou! Cancer cells are doing a new job again! This week, "Nature Nanotechnology" published a latest result from the Harvard Medical School research team[1].
For the first time, researchers discovered that cancer cells actually "stole" immune cells through nanotube structures between cells.
The mitochondria in this way strengthen themselves and weaken the immune function
.
Inhibiting the generation of nanotubes can form a synergistic effect with PD-1 inhibitors to further enhance the anti-tumor effect
.
In the comments distributed at the same time[2], two German scholars shouted that the cancer cell "Thirty-Six Strategies" had learned too well.
Isn't this a plan to draw a salary from the bottom of the pan? The English commentary surprises that the Chinese idiom must start with immunotherapy
.
We know that although the effect of immunotherapy is good, there are not many patients who can benefit from it, because there are so many tricks for cancer cells to evade immunity, and our existing immune checkpoint inhibitors (ICI) cannot be controlled.
The situation is understandable
.
The researchers started from their old profession and believed that understanding the communication between cancer cells and immune cells at the nanometer scale would definitely help to find a new immune escape mechanism, so they decided to start a simple small experiment—— Co-culture effector immune cells such as cancer cells and natural killer T cells, and use field emission scanning electron microscopy (FESEM) to observe the "emotional communication" between the co-cultured cells
.
Something interesting happened
.
Under FESEM, researchers found that there are many nanotube structures between cancer cells and immune cells.
These nanotubes range from 3-100μm in length and 50nm-2μm in width, and sometimes connect multiple immune cells at the same time
.
Moreover, because the nanotube structure is very fragile, it is likely to be damaged a lot during the experimental sample preparation stage.
The researchers believe that the existence of nanotubes in the actual situation should far exceed what is observed
.
Nanotubes between cancer cells and T cells Nanotubes can form multiple contact points with immune cells.
Thieves have never been seen walking away from the police.
I never heard that cancer cells are so aggressively establishing contact with immune cells.
, What do you want to do? It is not the first time that the nanotube structure between cells has been discovered
.
In previous studies, scientists have determined that nanotubes can help regulate the communication between immune cells [3]; the transfer of HIV between T cells [4], and the transfer of prions between neurons [5] Rely on nanotubes; of course, it is inseparable from the survival and metastasis of cancer cells [6-7]; nanotubes can also help cells exchange organelles[8], such as mitochondria
.
Mitochondria are the energy factories of cells.
A large number of documents have long emphasized the important influence of the quantity and quality of mitochondria on immune cell functions [9].
The expansion of CD8+ T cells, the production of cytokines, and effective anti-tumor immunity are very dependent.
Mitochondria
.
Thinking of this, researchers have a big alarm bell in their hearts, no, cancer cells won't be the mitochondria that steal immune cells, right? Using fluorescence to label the mitochondria in immune cells, the researchers really observed the transfer of mitochondria through the nanotubes, and this is completely the unilateral theft of cancer cells from immune cells.
In contrast, immune cells hardly get from cancer cells.
What to get
.
The yellow arrow indicates the transfer of mitochondria.
The researchers were initially worried about whether it was a misunderstanding caused by the extravasation of fluorescent dyes.
As a result, several different experimental programs were tested and the same phenomenon was observed
.
This is the first time it has been discovered that cancer cells can steal mitochondria from immune cells through nanotubes! The one on the right is a metastatic mitochondrial cancer cell.
This trick is really amazing
.
After stealing mitochondria from immune cells, the respiratory capacity of cancer cells is significantly improved, while the relative respiratory capacity of immune cells decreases
.
After 16 hours of co-cultivation, the number of immune cells was significantly reduced, and the growth ability of cancer cells was significantly improved
.
The growth ability of cancer cells (black) isolated in co-culture has been significantly improved.
From now on, stealing mitochondria is obviously one of the survival strategies of cancer cells.
Can new anti-tumor methods be developed to address this? The researchers tried to combine the drug L-778123, a drug that inhibits the production of nanotubes, and a PD-1 inhibitor, and conducted experiments in mice
.
Mice with 4T1 breast cancer were divided into 6 groups.
The PD-1 inhibitor doses were all 10 mg/kg, and L-778123 tested different doses (see the figure below)
.
The results show that L-778123 can form a significant synergistic effect with PD-1 inhibitors, and the effect is obviously dose-dependent with L-788123.
High doses of L-788123 can better enhance the anti-tumor effect of PD-1 inhibitors Effect
.
L-788123+PD-1 inhibitor can better inhibit tumor growth.
However, in experiments, L-788123 cannot completely prevent cancer cells from stealing mitochondria.
It can be seen that nanotubes are not the only mechanism of mitochondrial metastasis
.
As for what conspiracy is behind this, and why and how cancer cells learned this conspiracy, we have to wait for the follow-up research results
.
In any case, there are thousands of tricks for cancer cells, and one is one.
Reference materials: [1]https://#Sec25[2]https ://Önfelt, B.
, Nedvetzki, S.
, Yanagi, K.
& Davis, DM Cutting edge: membrane nanotubes connect immune cells.
J.
Immunol.
173, 1511–1513 (2004).
[4]Sowinski, S.
et al.
Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission.
Nat.
Cell Biol.
10, 211–219 (2008).
[5]Gousset, K.
et al.
Prions hijack tunnelling nanotubes for intercellular spread.
Nat.
Cell Biol.
11, 328–336 (2009).
[6]Osswald, M.
et al.
Brain tumour cells interconnect to a functional and resistant network.
Nature 528, 93–98 (2015).
[7]Connor, Y.
et al.
Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype.
Nat.
Commun.
6,8671 (2015).
[8]Rustom, A.
, Saffrich, R.
, Markovic, I.
, Walther, P.
& Gerdes, H.
-H.
Nanotubular highways for intercellular organelle transport.
Science 303, 1007–1010 (2004 ).
[9]Bantug, GR et al.
Nat.
Rev.
Immunol.
18, 19–34 (2018).
The author of this articleDai Siyu
For the first time, researchers discovered that cancer cells actually "stole" immune cells through nanotube structures between cells.
The mitochondria in this way strengthen themselves and weaken the immune function
.
Inhibiting the generation of nanotubes can form a synergistic effect with PD-1 inhibitors to further enhance the anti-tumor effect
.
In the comments distributed at the same time[2], two German scholars shouted that the cancer cell "Thirty-Six Strategies" had learned too well.
Isn't this a plan to draw a salary from the bottom of the pan? The English commentary surprises that the Chinese idiom must start with immunotherapy
.
We know that although the effect of immunotherapy is good, there are not many patients who can benefit from it, because there are so many tricks for cancer cells to evade immunity, and our existing immune checkpoint inhibitors (ICI) cannot be controlled.
The situation is understandable
.
The researchers started from their old profession and believed that understanding the communication between cancer cells and immune cells at the nanometer scale would definitely help to find a new immune escape mechanism, so they decided to start a simple small experiment—— Co-culture effector immune cells such as cancer cells and natural killer T cells, and use field emission scanning electron microscopy (FESEM) to observe the "emotional communication" between the co-cultured cells
.
Something interesting happened
.
Under FESEM, researchers found that there are many nanotube structures between cancer cells and immune cells.
These nanotubes range from 3-100μm in length and 50nm-2μm in width, and sometimes connect multiple immune cells at the same time
.
Moreover, because the nanotube structure is very fragile, it is likely to be damaged a lot during the experimental sample preparation stage.
The researchers believe that the existence of nanotubes in the actual situation should far exceed what is observed
.
Nanotubes between cancer cells and T cells Nanotubes can form multiple contact points with immune cells.
Thieves have never been seen walking away from the police.
I never heard that cancer cells are so aggressively establishing contact with immune cells.
, What do you want to do? It is not the first time that the nanotube structure between cells has been discovered
.
In previous studies, scientists have determined that nanotubes can help regulate the communication between immune cells [3]; the transfer of HIV between T cells [4], and the transfer of prions between neurons [5] Rely on nanotubes; of course, it is inseparable from the survival and metastasis of cancer cells [6-7]; nanotubes can also help cells exchange organelles[8], such as mitochondria
.
Mitochondria are the energy factories of cells.
A large number of documents have long emphasized the important influence of the quantity and quality of mitochondria on immune cell functions [9].
The expansion of CD8+ T cells, the production of cytokines, and effective anti-tumor immunity are very dependent.
Mitochondria
.
Thinking of this, researchers have a big alarm bell in their hearts, no, cancer cells won't be the mitochondria that steal immune cells, right? Using fluorescence to label the mitochondria in immune cells, the researchers really observed the transfer of mitochondria through the nanotubes, and this is completely the unilateral theft of cancer cells from immune cells.
In contrast, immune cells hardly get from cancer cells.
What to get
.
The yellow arrow indicates the transfer of mitochondria.
The researchers were initially worried about whether it was a misunderstanding caused by the extravasation of fluorescent dyes.
As a result, several different experimental programs were tested and the same phenomenon was observed
.
This is the first time it has been discovered that cancer cells can steal mitochondria from immune cells through nanotubes! The one on the right is a metastatic mitochondrial cancer cell.
This trick is really amazing
.
After stealing mitochondria from immune cells, the respiratory capacity of cancer cells is significantly improved, while the relative respiratory capacity of immune cells decreases
.
After 16 hours of co-cultivation, the number of immune cells was significantly reduced, and the growth ability of cancer cells was significantly improved
.
The growth ability of cancer cells (black) isolated in co-culture has been significantly improved.
From now on, stealing mitochondria is obviously one of the survival strategies of cancer cells.
Can new anti-tumor methods be developed to address this? The researchers tried to combine the drug L-778123, a drug that inhibits the production of nanotubes, and a PD-1 inhibitor, and conducted experiments in mice
.
Mice with 4T1 breast cancer were divided into 6 groups.
The PD-1 inhibitor doses were all 10 mg/kg, and L-778123 tested different doses (see the figure below)
.
The results show that L-778123 can form a significant synergistic effect with PD-1 inhibitors, and the effect is obviously dose-dependent with L-788123.
High doses of L-788123 can better enhance the anti-tumor effect of PD-1 inhibitors Effect
.
L-788123+PD-1 inhibitor can better inhibit tumor growth.
However, in experiments, L-788123 cannot completely prevent cancer cells from stealing mitochondria.
It can be seen that nanotubes are not the only mechanism of mitochondrial metastasis
.
As for what conspiracy is behind this, and why and how cancer cells learned this conspiracy, we have to wait for the follow-up research results
.
In any case, there are thousands of tricks for cancer cells, and one is one.
Reference materials: [1]https://#Sec25[2]https ://Önfelt, B.
, Nedvetzki, S.
, Yanagi, K.
& Davis, DM Cutting edge: membrane nanotubes connect immune cells.
J.
Immunol.
173, 1511–1513 (2004).
[4]Sowinski, S.
et al.
Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission.
Nat.
Cell Biol.
10, 211–219 (2008).
[5]Gousset, K.
et al.
Prions hijack tunnelling nanotubes for intercellular spread.
Nat.
Cell Biol.
11, 328–336 (2009).
[6]Osswald, M.
et al.
Brain tumour cells interconnect to a functional and resistant network.
Nature 528, 93–98 (2015).
[7]Connor, Y.
et al.
Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype.
Nat.
Commun.
6,8671 (2015).
[8]Rustom, A.
, Saffrich, R.
, Markovic, I.
, Walther, P.
& Gerdes, H.
-H.
Nanotubular highways for intercellular organelle transport.
Science 303, 1007–1010 (2004 ).
[9]Bantug, GR et al.
Nat.
Rev.
Immunol.
18, 19–34 (2018).
The author of this articleDai Siyu
