Nature Nanotechnology: I was stunned. Cancer cells learned 36 tricks. They took money from the bottom and stole the mitochondria of immune cells to achieve immune escape.

"The Thirty-Six Strategies" is a collection of ancient Chinese war wisdom.
The ancients even distilled these war strategies into short proverbs, such as: concealing the sky, keeping secrets, making things out of nothing, and drawing salaries from the bottom of the pan
.

These strategies teach us how to defeat the enemy with wisdom on the battlefield and even in life

Among them, the salary draw from the bottom of the kettle comes from the nineteenth plan of the "Thirty-Six Measures", which means to draw the firewood from the bottom of the pot to stop the water from boiling
.

The essence of this tactic is not to directly attack the enemy's combat forces, but to weaken their ability to wage war by destroying the enemy's logistics

On November 18, 2021, researchers from Harvard Medical School in the United States published a research paper titled Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells in the journal Nature Nanotechnology .

Nature Nanotechnology Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells

The study provides evidence that cancer cells cleverly use the tactical strategy of "drawing money from the bottom" to steal the mitochondria of T cells (cell energy factories) through nanotubes, which not only strengthens itself, but also weakens the activity of immune cells, so as to outwit the immune system.

System to achieve immune escape

With the development of life sciences, scientists have deepened their understanding of immunity, metabolism and tumors
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Previously, a large number of studies have emphasized that mitochondria are vital to the metabolism and activation of immune cells

Hard power is important when the two armies are facing each other, but strategizing is also the key to victory
.

Faced with the suppression of the firepower of the immune system, will cancer cells evolve a mechanism to weaken them and then outwit the immune system?

In this study, the research team first noticed mitochondrial transfer, an easily overlooked intercellular communication phenomenon
.

They established a simple co-culture system in which immune cells are labeled with fluorescent dyes and selectively aggregate in mitochondria

Fluorescent dye traces show the contact between tumor cells and immune cells

Fluorescent dye trace shows the contact between tumor cells and immune cells.
Fluorescent dye trace shows the contact between tumor cells and immune cells.

They found that when immune cells and tumor cells are co-cultured, the mitochondria of immune cells transfer to tumor cells
.

In order to rule out the false positive results caused by the leakage of non-specific free dye, the transfer of the fluorescently labeled mitochondrial protein, Dendra2 green-labeled cytochrome c oxidase subunit 8 was also discovered

The combination of these different tracing methods confirms that the phenomenon seen is real, that is, tumor cells will "steal" the mitochondria of immune cells in some way
.

Tumor cells hijack the mitochondria of immune cells through nanotubes

Tumor cells hijack the mitochondria of immune cells through nanotubes Tumor cells hijack the mitochondria of immune cells through nanotubes

Therefore, the research team further explored the ways in which tumor cells “drained from the bottom” of immune cells
.

Mitochondrial transfer between cells involves multiple mechanisms, including gap junctions, nanotubes, cell fusion, and extracellular vesicles

Under the electron microscope, cancer cells and immune cells are connected by physical nanotubes

Then, the research team targeted to knock out the genes for nanotube formation (Sec3, Sec5) and mitochondrial transport (Miro1), and the phenomenon of mitochondrial transfer disappeared
.

Based on these evidences, the researchers clearly established a causal link, that is, tumor cells use nanotubes to "steal" the mitochondria of immune cells
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More importantly, the research team also pointed out that this mitochondrial hijacking phenomenon does not only occur in the in vitro co-culture system, but also occurs in the body, thus emphasizing its clinical relevance
.

After inhibiting the formation of nanotubes (knockout Sec3, Sec5, Miro1 genes), tumor cells can no longer steal the mitochondria of immune cells

After inhibiting nanotube formation (knock out Sec3, Sec5, Miro1 genes), tumor cells can no longer steal immune cell mitochondria.
Inhibit nanotube formation (knock out Sec3, Sec5, Miro1 genes), tumor cells can no longer steal immune cell mitochondria

Now that the tactical strategies of tumor cells have been discovered, how can we prevent them from "drawing from the bottom"?

In fact, before this, many studies have found some inhibitors that inhibit the formation of nanotubes, which can prevent this immune escape strategy of tumor cells
.
The research team verified this theory in an adenocarcinoma model by using an anti-PD-1 antibody in combination with a nanotube inhibitor-L-778123
.

They found that at non-cytotoxic concentrations, L-778123 can effectively inhibit the formation of nanotubes
.
Compared with treatment alone, L-778123 combined with PD-1 inhibitors significantly increased the activation and infiltration of T cells in tumors, leading to delayed tumor progression and prolonged survival time of tumor animal models
.

L-778123 combined with PD-1 inhibitors leads to delayed tumor progression and prolonged survival time of tumor-bearing animals

L-778123 combined with PD-1 inhibitors leads to delayed tumor progression and prolonged survival time of tumor-bearing animals L-778123 combined with PD-1 inhibitors leads to delayed tumor progression and prolonged survival time of tumor-bearing animals

Although the systemic administration and non-specificity of L-778123 hinder clear conclusions about its mechanism of action, these findings clearly indicate the potential therapeutic value of the combination therapy
.
The research team said that a more specific and targeted method can be used to deliver inhibitors directly to tumors in the body, thereby avoiding its side effects
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Nanotube inhibitor L-778123 combined with PD-1 inhibitor can enhance the effect of anti-tumor treatment

Nanotube inhibitor L-778123 combined with PD-1 inhibitor can enhance the anti-tumor therapeutic effect Nanotube inhibitor L-778123 combined with PD-1 inhibitor can enhance the anti-tumor therapeutic effect

All in all, this latest study shows that cancer cells can capture the mitochondria of immune cells through nanotube-mediated hijacking, thereby weakening the immune capacity of immune cells
.
It's like cancer cells have also learned the "Thirty-Six Strategies" and skillfully use "drawing from the bottom" to strengthen themselves and weaken their opponents, so as to achieve immune escape
.

In follow-up studies, the research team also confirmed that the nanotube inhibitor L-778123 can be combined with PD-1 inhibitors to enhance the immune system's ability to kill tumor cells, and it may become a brand new anti-tumor treatment in the future
.

Original source:

Original source:

Baldwin, JG, Gattinoni, L.
Cancer cells hijack T-cell mitochondria .
Nat.
Nanotechnol.
(2021).
https://doi.
org/10.
1038/s41565-021-01006-y.

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