Nature: Interleukin-18 or become a new immune hot spot! Yale scientists have broken through the "bait receptors" secreted by cancer cells and found promising new immune checkpoints. Scientific discoveries.

More than a decade ago, scientists discovered a cytokine called Interleukin-18 (IL-18), which enhances the immune function of T cells and NK cells in experiments, and is regarded as a black horse of tumor immunotherapy.relying on the human immune system to defeat cancer is the pursuit of countless people, so the clinical trials of IL-18 in the fight against cancer began soon.however, the phase II trial of IL-18 was extremely disastrous.no matter how much the use of IL-18 is increased, only 1 out of 60 patients with melanoma has achieved partial remission [1].drug research and development was quickly stalled, but this made Aaron king, an immunologist at Yale University, into thinking: why can't IL-18 work when other recombinant human interleukin drugs can be used in clinical practice? Ten years later, the team led by Aron King finally solved the mystery. Their latest paper published in nature pointed out that the reason why IL-18 failed to play an anti-tumor role was that after it entered the body, cancer cells would secrete a large number of IL-18BP, the receptor of IL-18, which competitively binds to IL-18, and snatched away the immune promoting effect that IL-18 should have played! In other words, the "bait" released by cancer cells makes IL-18BP a "secretory immune checkpoint" in the tumor microenvironment.from 250 million variants of IL-18, the research team screened out a special type of dr-18 that would not combine with bait. It was used in combination with PD-1 inhibitor, and achieved good curative effect in the experiment [2].when IL-18 goes to the left, it will deviate, and it will be on the right. In fact, this situation faced by IL-18 is similar to the familiar PD-1 / L1.in tumor microenvironment, PD-L1 is expressed in cancer cells, T cells, macrophages and even dendritic cells, but their significance is obviously different.for example, recent studies have shown that the inhibitory effect of PD-L1 on dendritic cells may be much greater than that of macrophages [3].now we can detect the expression of PD-L1, including TPS, ICs and CPS.and when IL-18 enters the tumor microenvironment, there are also two kinds of receptors to distinguish. The friendly army is the normal receptor IL-18R on the surface of T cells and NK cells, while the enemy is the bait IL-18BP released by cancer cells.however, under normal conditions, the affinity of IL-18BP to IL-18 is much higher than that of IL-18R.the friendly forces who came to reinforce the immune system were pulled to the side of the enemy. How can we fight this battle? The team analyzed the TCGA database and found that although IL-18R is widely expressed in immune cells, IL-18BP is more widely distributed in various solid tumors.in order for IL-18, a powerful immune promoting molecule, to play a role, we must find a way to bypass the bait released by cancer cells, so as to break through the limit of IL-18BP, the immune checkpoint.the research team hopes to find a molecule that only binds to IL-18R and does not bind to bait IL-18BP. To this end, the directed evolution method was used to screen a IL-18 variant named dr-18, which has strong affinity with IL-18R, from more than 250 million IL-18 variants.for the knowledge of directed evolution, you can check the relevant information of the 2018 Nobel Prize in chemistry ~ the experiments conducted on mouse models of melanoma and colorectal cancer show that this dr-18 is indeed excellent, and its efficacy when used alone is no less than that of PD-1 inhibitors.if combined with PD-1 inhibitor, it can kill most of the tumors in mice! Dr-18 and ancestor IL-18 are not the least effective. Further analysis shows that dr-18's excellent anti-tumor effect comes from its full mobilization of CD8 + T cells, NK cells, tumor stem cell like T cells and other immune cells. at the same time, dr-18 also changed the immune microenvironment and severely suppressed the immunosuppressive cells. Marcus bosenberg of Yale University, one of the authors of the paper, said that dr-18 can activate NK cells and stem cell like T cells in tumor, which is difficult to achieve by existing immunosuppressants, so it has great value in the treatment of "cold tumor" [4]. experts in the industry also highly praised this study and thought that it had a good prospect of clinical transformation. Aaron king, who led the study, announced that he would establish a new biotechnology company, striving to push this therapy into clinical trials next year and test the efficacy in actual combat [5]. cancer cells, cancer cells, you can always make some new tricks. but I don't believe the odd cake. I'm 358 I'm sorry. I'm in the field. most of the earth's scientists have been mobilized, and sooner or later they will clean you up, hum. the audio course "8 lectures on small cell lung cancer" which was built by the singularity cake for 3 months, is coming online. 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