"Cell" Subsidiary: This is a tragic story of a T cell deep inside the cancer tissue, and the grain supply has to rely on fatty acid metabolism.

Release date: 2017-10-18

As soon as the tumor enters the sea, all the skills are zero. - 奇点糕

The above sentence is a profound summary of the anti-cancer performance of T-cells.

A year ago, we wrote an article about the sad story of a depleted state when a killer T cell enters a tumor and is "brainwashed" by the tumor.

Recently, Professor Hildegund Ertl from the Wistar Institute of the United States and Dr. Zhang Ying, a Chinese scientist, have revealed that the situation of T cells in tumors is not only tragic, but also tragic.

Professor Hildegund Ertl

We all know that the tumor is a metamorphosis and evil tissue. The low sugar and low oxygen inside, the normal cells can hardly adapt to this abnormal environment. T cells that need a lot of energy to play to kill the enemy skills are more difficult to adapt to this environment.

Dr. Zhang found that after receiving a drug that stimulates the immune system, a large number of activated killer T cells enter the tumor, but after about 30 days, the number of killer T cells in the tumor is reduced by about 90%. Where are the large numbers of T cells going? Quietly left? Still heroic and dead? The researchers are not clear.

But the researchers found that the remaining part of the killing T cells, in order to preserve the last "revolutionary" fire, changed their "food" habits, from the metabolic strategy of glucose-powered to fatty acid metabolism. Energy supply, survive in the cracks. Surprisingly, when Dr. Zhang further activated the T-cell fatty acid metabolism pathway through drugs, they were awakened. This important research was recently published in the famous journal Cancer Cell [1].

Dr. Zhang Ying

In fact, last December's Dana-Farber Cancer Institute [2] and the University of Pennsylvania School of Medicine team [3], two back-to-back studies in the journal Science on T cell depletion have pointed out that due to persistent antigens Stimulated, the T cells that entered the tumor were reprogrammed. In layman's terms, it was "brainwashed" and no longer had the ability to kill tumors.

Their findings explain to a certain extent that immunological checkpoint inhibitors (PD-1 and PD-L1 antibodies) have low response rates for cancer treatment, and CAR-T cannot cure solid tumors. But they did not answer whether the reprogramming of this T cell can be broken? Or we can write them back. If you can, we can completely liberate T cells and greatly enhance the effectiveness of immunotherapy.

From Dr. Zhang's research, this reprogramming seems to be solvable.

Professor Ertl said, "There is little research on the mechanism of T cell depletion. Given that T cells are essential for the immunotherapy of cancer, our results will be important to improve the efficiency of immunotherapy! We will conduct corresponding tests in the future. The T cells are pre-treated with fatty acid metabolism and then transferred to the patient to explore whether this will prolong the survival time of T cells, improve their function, and ultimately benefit patients."[4,5]

Scientists already know that the presence of T cells in the tumor microenvironment is often associated with better clinical outcomes and better patient response to drugs.

However, the premise that T cells want to function is to have enough energy. Glucose is often the cell's preferred source of energy because it produces energy at a very high rate for cells to perform their functions.

However, in the tumor microenvironment, the supply of oxygen and glucose is significantly insufficient due to fewer blood vessels. In addition, the madness of tumor cells has increased the situation of hypoxia and low sugar. In this case, it is difficult for T cells to acquire energy through glucose metabolism.

So, in the face of this dilemma, is there any other trick for T cells? This is also a problem that plagues the team of Professor Ertl.

To clarify this issue, Professor Ertl led the team to first inoculate normal mice and melanoma mice carrying the B16-BrafV600E gene mutation with two adenoviral vaccine mixtures to stimulate melanoma-associated antigen-specificity in mice (MAA). T cells and virus antigen-specific (E7) T cells. Vaccination can slow the growth of tumors on the one hand, and the status of T cells in tumors on the other hand.

Thirty days after vaccination, mice carrying genetic mutations have a 90% reduction in the number of killer T cells that can produce enemy weapons such as granzyme, perforin, and gamma interferon, but factors that inhibit T cell function. The expression of PD-1 and LAG3 has increased. That is, T cells are indeed "tired", resulting in T cell depletion.

After T cells enter the tumor, they recover their fighting power by burning fatty acids (FA) under the stimulation of PPARa agonists.

Fortunately, however, although T cells are "tired", the specificity of the antigen they target has not changed! The researchers speculate that in addition to sustained antigenic stimulation, there must be other factors driving T cell depletion.

Subsequent findings confirm their hypothesis: The researchers found that T cells in tumors, whether MAA-T cells or E7-T cells, increased their expression of hypoxia-inducible factor 1α (HIF1α). Further studies found that HIF1α promoted the expression of LAG3, but had no effect on the expression of PD-1. At the same time, HIF1α also destroyed the function of T cells to release enemy weapons.

In other words, under hypoxic conditions, high expression of HIF1α leads to the loss of anti-tumor function of T cells!

More interestingly, the researchers found that when the HIF1α gene was knocked out, in addition to changes in glucose metabolism, T cells promoted fatty acid metabolism and uptake-related key transcription factors, PPARα, and expression increased. This has led researchers to wonder whether T cells in tumors have shifted from efficient glucose metabolism to relatively inefficient fatty acid metabolism.

After T cells enter the tumor, the fatty acid (FA) metabolism is enhanced by stimulation with PPARa agonists.

Therefore, the researchers used liquid chromatography to analyze the T cell metabolism in tumors of mutant mice. They found that 30 days after inoculation, T cells in the tumor, sugar metabolites decreased, and fatty acid metabolites increased.

To further validate this result, the researchers also performed fatty acid levels on tumor samples from different stages of genetically modified melanoma mice, tumor samples from melanoma-derived xenografts at different stages, and tumors and serum samples from patients with metastatic melanoma. Detection. The results all show that the level of free fatty acids continues to increase during tumor progression. In other words, it is indeed feasible for T cells to rely on fatty acid metabolism to supply energy.

Combining these two results, we can easily understand that in the face of the harsh environment of hypoxia and low sugar in the tumor, T cells lack the supply of glucose, and the function of glucose metabolism does not work. It is forced to use, and more and more use of the environment Fatty acids, which are powered by fatty acid oxidation, live in the world.

(Left) In the environment of low glucose and hypoxia, the fatty acid metabolism is weak, and the killing ability of T cells (purple) is low.

(Right) In the environment of low glucose and hypoxia, the fatty acid metabolism is strong, and the killing ability of T cells (purple) is strong.

Then enhance fatty acid oxidation, can it improve the anti-tumor function of T cells in the tumor microenvironment? Therefore, the researchers fed the experimental mice daily with PPARa agonists that increased fatty acid oxidation, and the control group was fed with dilutions; after 3 weeks of continuous mice, the spleens of the mice were removed and transferred to melanoma mice to find PPARa agonists. The treatment not only enhances the fatty acid metabolism of T cells, but also enhances the anti-tumor function of T cells. In addition, the researchers also confirmed that PPARa agonists specifically target T cells in the tumor microenvironment and do not work on other T cells.

Finally, the researchers compared the effect of pre-treatment with PPARa agonists on T cells combined with PD-1 inhibitors in the treatment of melanoma mice, and found that the combination of the two used to delay tumor progression and prevent about 50% of the small The growth of mouse tumors.

This study shows that in the face of the harsh conditions in the tumor microenvironment, T cells can take a different approach and survive by using fatty acid oxidation capacity. If we help it, increase its fatty acid oxidation capacity, and at the same time lift the tumor cell PD-1 on it, then the T cell will once again pick up the weapon that kills the tumor cells, and it will be charged! This is important for improving the therapeutic effect of immune checkpoint inhibitors or improving CAR-T treatment of solid tumors [6]!

Reference material

[1] Zhang Y, Kurupati R, Liu L, et al. Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy [J]. Cancer Cell, 2017, 32(3): 377- 391. e9.

[2] Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, et al. 2016. The epigenetic landscape of T cell exhaustion. Science 354:1165-9

[3] Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, et al. 2016. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354:1160-5

[4]https://

[5] Bradley CA. 2017. Immunotherapy: CD8+ T cells [mdash] burn fat, get fit. Nat Rev Cancer advance online publication

[6] Bailis W, Shyer JA, Chiorazzi M, et al. No Oxygen? No Glucose? No Problem: Fatty Acid Catabolism Enhances Effector CD8+ TILs[J]. Cancer Cell, 2017, 32(3): 280-281.

Source: Singularity Network (micro signal geekheal_com)

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