Immunity: Tumors lose their anti-cancer ability after ingesting by the production of harmful fats

In recent years, breakthroughs in cancer immunotherapy have revealed the powerful effectiveness of using immunity to fight cancer
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Unfortunately, only a small percentage of cancer patients respond to immunotherapy.

Metabolic changes are a major feature of cancer.
A common metabolic change in the tumor microenvironment (TME) is lipid accumulation, which can lead to lipid peroxidation.
This is closely related to immune dysfunction, but the specific mechanism is still unclear
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On June 7, 2021, Susan Kaech from the Salk Institute for Biological Research in the United States and Cui Guoliang from the German Cancer Institute, as co-corresponding authors, published the title: Uptake of oxidized lipids by the scavenger receptor CD36 promotes in the top immunology journal Immunity Research paper on lipid peroxidation and dysfunction in CD8+ T cells in tumors
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The study revealed a new tumor immunosuppressive mode.
The tumor microenvironment produces a large amount of "harmful lipids".
CD36 on the surface of CD8+ T cells absorbs these harmful oxidized low-density lipoproteins and induces lipid peroxidation and p38 kinase.
The downstream activation of the anti-tumor function of immune cells is inhibited
.

This discovery opened up a new way for a new type of cancer immunotherapy

First, in order to understand which types of lipid immune cells respond to tumor microenvironment (TME) exposure, the research team analyzed the composition and abundance of various lipids in tumor tissue fluid (TIF) and found that TIF contains multiple types of Lipids
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It may be that the availability of lipids has increased.
CD8+ tumor infiltrating lymphocytes (TILs) have combined more lipids, especially lipid peroxides, indicating that CD8+ T cells in tumors can adapt to high-fat tumor microbes by promoting lipid uptake and storage Environment (TME)
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With the failure of CD8+ TILs, transcripts encoding CD36 gradually accumulate
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Therefore, the research team guessed that the failing CD8+ TILs increased the expression of CD36 to adapt to the tumor microenvironment

To test this idea, the research team observed that CD8+ TILs from a variety of mouse and human tumors up-regulated the expression of CD36, indicating that CD36 is a characteristic of depleted CD8+ TILs in mice and humans
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Next, the research team used various methods to study how CD36 impairs the function of killer T cells
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They created a mouse model that lacked CD36 on T cells and used antibodies to block CD36

They confirmed that CD36 promotes T cell dysfunction in tumors by increasing the uptake of oxidized lipids, which leads to greater lipid oxidation and damage in T cells, and triggers the activation of stress response protein p38
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Lipid peroxide can also cause iron death.
Glutathione peroxidase 4 (GPX4, a key molecule that removes oxidized lipids in cells) can save cells from iron death by degrading lipid peroxides
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By analyzing publicly available transcriptome data, the research team found that decreased GPX4 expression is related to T cell exhaustion
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Through overexpression of GPX4, the research team found that the effector function of T cells after oxidized low-density lipoprotein (OxLDL) treatment was rescued, indicating that inhibition of lipid peroxidation can rescue the anti-tumor function of CD8+ TILs

Overall, the study revealed a new immunosuppressive mode in the tumor microenvironment (TME): CD8+ tumor infiltrating lymphocytes (TILs) increase the uptake of oxidized lipids, which may be caused by increased lipid oxidation in tumors , Leading to up-regulation of lipid peroxidation, activation of p38 kinase and dysfunction of CD8+ TILs
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This study uses antibody therapy to block CD36 or overexpression of GPX4 to reduce lipid oxidation, which can restore the function of killer T cells in tumors, elucidating the immunomodulatory effect of oxidized lipids in cancer

Original source:

Original source:

Shihao Xu, et al.

Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors.
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