Immune cells "instigated" by cancer cells may be used for cancer treatment

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Immune cells “instigated” by cancer cells may be used for cancer treatment

Introduction:

A study by Ludwig Cancer Research has discovered a method by which cancer cells can transform macrophages (a type of immune cell) from tumor destroyers Become a supporter of tumor growth and survival.

This research was published in the latest issue of “Nature Immunology”, entitled “Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity”.

Immune cells "instigated" by cancer cells may be used for cancer treatment.

The study was led by Ping-Chih Ho and postdoctoral researcher Giusy Di Conza from Lausanne – Ludwig Institute for Cancer Research. They found that in a mouse model of skin cancer melanoma, this type of macrophages in the tumor The transformation is driven by lipids released by cancer cells.

The study also identified some key activities and participating molecules that promote this “polarization” of tumor-associated macrophages (tumor-associated macrophages, TAM). Ho and Di Conza and colleagues showed that β-glucosylceramide binds to receptors on TAM and triggers a stress response in a tubular organelle called the endoplasmic reticulum (ER). This in turn triggers at least two signal cascades within the cell to drive the expression of genes in macrophages and promote their transformation.

“In addition to revealing the previously unknown mechanism by which tumors manipulate the immune system for their own benefit, our research has also identified a signal transduction mechanism that can push macrophages back to their anti-tumor phenotype through drug targeting for cancer treatment. .” said Di Conza, the first author of the paper.

When Ho and Di Conza and colleagues began these studies, they observed that TAM that promotes tumor development showed two strange characteristics: higher lipid content than usual, and endoplasmic reticulum swelling. Swelling is usually a sign of endoplasmic reticulum stress, and the research team also detected elevated levels of stress proteins in TAM that promote tumor development. Stress proteins (XBP1’s form of suppressing immune cell function) appear to be necessary to bias TAM towards a state or phenotype that promotes tumor development.

These observations are consistent with other emerging evidence that abnormal lipid metabolism in cancer cells can lead to the accumulation of lipids in the tumor microenvironment, thereby suppressing anti-tumor immunity.

The connection between cancer cells and macrophages

Di Conza said, “We know that metabolites in tumors are not only important for the formation of tumor phenotypes, but also important for immune cells that exist in the tumor microenvironment. Therefore, we want to know the difference between cancer cells and macrophages. Whether there is a metabolic link between them can instruct macrophages to become their helpers.”

The research team tested this possibility by removing lipids from the conditioned medium used to grow mouse tumor cells. Doing so can prevent TAM from transforming into a phenotype that promotes tumor development.

Next, the research team tried to determine the specific lipids that trigger TAM polarization. Unexpectedly, the COVID-19 pandemic helped them complete this difficult task. With no access to the laboratory during the pandemic lockdown, Di Conza spent some time reviewing genetic data related to lipid identification and binding. In the process, she found a new clue.

A lipid receptor called Mincle was found on the surface of macrophages, and its activity was significant when exposed to the culture medium in which mouse cancer cells were grown. Mincle can induce the endoplasmic reticulum stress response and the accumulation of lipids in macrophages, which are the characteristics that Di Conza and his team have observed in TAM that promotes tumor development.

When the researchers used antibodies to block the activity of Mincle, they observed a significant decrease in TAM polarization to promote tumor development.

Mincle’s discovery prompted researchers to further study β-glucosylceramide, a lipid that is released into the tumor microenvironment and binds to Mincle. Inhibiting its production resulted in a decrease in TAM that promotes tumor development and slowed tumor growth in mice.

Associate researcher Ho of Ludwig Cancer Research Center said, “Based on this discovery, we speculate that cancer cells increase the metabolism of this lipid, and then the secretion of β-glucosylceramide will notify the surrounding cells that these cancer cells need help. It It also helps to promote the functional transformation of macrophages in the tumor microenvironment, thereby becoming cells that promote tumor development.”

XBP1 is not the only “participant”

Subsequent experiments further found that XBP1 is activated in TAM that promotes tumor development, and removal of this gene can slow tumor growth. This indicates that XBP1 is not only essential for TAM polarization, but also supports cancer cell survival.

In addition, XPB1 alone is not enough to promote macrophages to form a phenotype that promotes tumor development. Other experiments have shown that another signal cascade cooperates with the signal cascade of XBP1 to induce TAM polarization. Facts have proved that this is a pathway involving signal protein and transcription factor STAT3, which binds to DNA and directly regulates gene expression.

Now that some key activities and participating molecules in TAM polarization have been identified, it is possible that drug targeting can slow down or even reverse this process.

Reference:

https://www.nature.com/articles/s41590-021-01047-4#Sec33

Immune cells “instigated” by cancer cells may be used for cancer treatment.

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