Jonathan D. Powell's team of Johns Hopkins University School of Medicine published important research results in the top journal Science. They found that JHU083, a small molecular compound that blocks glutamine metabolism, can disrupt tumor metabolism, paralyze tumor's "Warburg effect", reverse tumor microenvironment's hypoxia, acidosis and malnutrition, and relieve tumor microenvironment's immunosuppression ability.
In addition, this small molecule can reprogram the metabolic mode of T cells, activate T cells directly (yes, directly, without tumor stimulation), make T cells live longer and promote the formation of memory T cells. In other words, JHU083 has the functions of destroying tumor microenvironment and activating immune system. To put it more clearly, JHU083 can not only break the drug resistance of tumor to immune checkpoint inhibitors, but also activate T cells to kill cancer cells by its own strength.
In the author's opinion, this study reveals a huge difference in metabolic plasticity between cancer cells and T cells.
The author also gave this treatment a foreign name "metabolic checkpoint" inhibitor.
So how was this metabolic checkpoint inhibitor born? What is the anti-cancer effect? What is the magical mechanism behind it?
If tumor is an evil castle, then microenvironment is its moat.
The tumor microenvironment with low oxygen, acidity and lack of nutrients is a free and unfettered place for tumors, but a barren place for immune cells.
Immunotherapy is ineffective for many patients, and tumor microenvironment is "indispensable".
The formation of tumor microenvironment depends on the special metabolic mode of tumor, which is also known as "Warburg effect".
To sum up in one sentence, that is: the special metabolic mode of tumor has shaped the tumor microenvironment which can promote tumor growth and inhibit the immune system.
Aiming at tumor metabolism is an important way to eliminate tumor.
This method should have been thought of by scientists not long after Warburg discovered abnormal tumor metabolism.
Scientists have noticed that because glucose is metabolized into lactic acid by glycolysis in tumors, glutamine can promote the circulation of tricarboxylic acid and generate metabolic intermediates, which can be used to synthesize lipids, protein, nucleic acids and other substances that are essential for cell growth and proliferation.
Therefore, many scientists speculate that blocking glutamine metabolism may inhibit the growth of tumors and even relieve the suppression of tumors on the immune system. The first thing that everyone thinks of is to get the glutaminase, but unfortunately the effect is not very good. Because tumors that have been evolving will always bypass this target, it is easy to be resistant.
The only way is to completely block glutamine metabolism, that is, to simultaneously inhibit a variety of enzymes related to glutamine metabolism. DON(6-Diazo-5-oxo-L-norleucine) is such a compound.
Unfortunately, although DON does show extraordinary anti-tumor effect, its toxicity is unbearable. After all, the metabolic mode of tumor is the same as that of normal cells in many places.
In order to avoid DON's systemic toxicity, Powell team made some modifications to DON and turned it into a "prodrug". This "prodrug" needs to enter the tumor microenvironment and be treated by special enzymes before it can be changed back to DON, which can reduce the toxicity of glutamine metabolic pathway inhibitors.
Thus JHU083 was born.
Theoretically, there is nothing wrong with this design. What is the anticancer effect of JHU083? Are there really no side effects?
Powell's team made in-depth research in four cancer cell lines: colon cancer MC38, lymphoma EL-4, colon cancer CT26 and melanoma B16. After inoculating four kinds of cancer cells in mice, injecting JHU083 has a good anti-cancer effect, and the survival rate of all types of mice is significantly improved. And the anti-cancer effect is very lasting (please remember silently).
Through metabolic analysis, the researchers found that JHU083, a glutamine metabolic inhibitor, inhibited glucose metabolism through tricarboxylic acid cycle and glycolysis.
Not only is the normal metabolism chaotic, but the tumor-dependent "Warburg effect" is also paralyzed.
Subsequently, the contents of glutamine and glucose in the tumor increased significantly, and the hypoxia state of the tumor also improved significantly. JHU083 not only cut off the tumor energy, but also transformed the tumor microenvironment, turning the "barren" land into a "rich" land.
Since JHU083 has improved the tumor microenvironment, the first application that researchers think of is naturally: combined immunotherapy! !
From the above results, JHU083 can definitely improve the effect of immunotherapy, and maybe it can also relieve the drug resistance of tumors to immunotherapy.
The researchers did not hesitate to choose MC38 which was resistant to PD-1 inhibitor.
However, at this time, the way of administration made the researchers hesitate. Is it to be administered together, or should JHU083 be used first and then PD-1 inhibitor? After all, the metabolic process of T cells is also connected with cancer cells . Maybe, the T cells that PD-1 inhibitor finally saved were completely killed by JHU083 again.
So they tried both methods of administration. Guess what the result is.
Surprised the researchers.
In any case, it was unexpected that JHU083 and PD-1 inhibitor had the best effect when administered at the same time. When JHU083 and PD-1 inhibitor were used together, the complete remission rate of mice inoculated with MC38 was close to 100%.
This result makes the researchers have an unexpected discovery, although glutamine metabolism will promote the proliferation of lymphocytes and enhance the activity of lymphocytes; But now it seems that inhibiting glutamine metabolism will not only have a negative effect on immune cells, but also enhance the function of immune cells. Combined with JHU083 single drug therapy found earlier, mice will get lasting anti-tumor effect.
All these indicate that JHU083 may still be an immunotherapy drug.
The researchers quickly confirmed this in mice. Moreover, the anti-tumor activity of JHU083 is completely dependent on CD8+ T cells. In other words, JHU083 enhances the anti-cancer ability of the immune system only by affecting the metabolism of tumors and T cells.
So what changes did JHU083 make on CD8+ T cells?
First, Powell's team confirmed that the infiltration of CD8+ T cells in the tumor increased after JHU083 treatment, which should be the result of the improvement of tumor microenvironment. Moreover, among these tumor infiltrating T cells, there are more antigen-specific ones.
Then, they isolated CD8+ tumor infiltrating T cells from mice treated with JHU083 and mice not treated with JHU083. Then I did RNA sequencing. It was found that there were significant differences in the expression of 4313 genes between them.
After careful analysis, it is easy to find that the transcriptome of CD8+ tumor infiltrating T cells in mice treated with JHU083 shows the characteristics of enhanced proliferation, enhanced anticancer activity and non-exhaustion. In addition, the proportion of double-positive T cells in PD-1 and LAG-3 immune checkpoints is low, IFNγ is increased, and anti-cancer substances such as granzyme B and IL-2 are increased. In addition, the researchers also observed that the expression of genes related to long-lived memory T cells increased, while the expression of genes related to apoptosis decreased significantly.
To the researchers' surprise, JHU083 can activate T cells to produce most of the above reactions even in the absence of tumor cells. It doesn't depend on the stimulation of tumor cells. It's completely independent.
The above research results are actually very exciting. After all, we found a drug that can destroy the tumor microenvironment and enhance the anti-cancer effect of T cells.
However, seeing the above research results, a bigger question lingers in the minds of researchers.
The way JHU083 plays its role is to affect metabolism, so why is its influence on cancer cells and T cells so different?
In order to solve this problem, the researchers did super complicated experiments. I'm afraid I need 2000 words to explain the experimental process clearly, so I'll omit the research process here and just say the conclusion.
The conclusion is that for cancer cells, the dependence between glycolysis, oxidative phosphorylation and glutamine metabolism is seriously lacking in plasticity. As long as it is messed up, it will be completely finished. Isn't this a bit like a gangster? If one place is chaotic, it will be completely chaotic.
T cells are different, and their metabolic plasticity is very strong. After glutamine metabolism is blocked, adaptive metabolic reprogramming will occur immediately, thus enhancing survival, proliferation and anti-cancer skills.
Finally, let me sum up.
This time, the Powell team discovered a small molecule drug that can not only change the tumor microenvironment, but also directly enhance the anti-cancer effect of immune cells. We can say that it is an immunotherapy, and it has the ability to transform the tumor microenvironment.