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Immune evasion in cancer is really interesting and particularly important because immune therapy has really emerged as a groundbreaking therapy. But, while immu
by bglazer 3y ago
Immune evasion in cancer is really interesting and particularly important because immune therapy has really emerged as a groundbreaking therapy. But, while immunotherapy excels in blood cancers, it still struggles in solid tumors. Part of the reason for this is that a solid group of cancer cells can much more easily change their microenvironment to exclude immune cells.
So this paper explores one of the ways they do that. Cancer cells turn off a protein that sits on the surface of normal human cells that immune cells regularly bind to. Binding to this protein, CD58, causes changes in the immune cell. What these changes are critically depends on the other signals that the immune cell senses on the surface of the cell. If it senses another (somewhat famous) protein, PD-L1, the immune cell self destructs, as PD-L1’s presence typically means that a cell is normal and healthy. But, cancer cells frequently evolve to over generate PD-L1, thereby creating an micro-environment filled with self destruct signals. Further, the other protein CD58 actually increases the physical force of immune cell binding, so when cancer cells turn off CD58 they actually get more slippery.
This paper explores an interesting connection between the two proteins. There’s a third protein which binds to both of them and increases the amount of time they're active on the cell’s surface. Honestly I haven’t had time to fully digest this bit, but it seems like the regulatory protein preferentially binds to CD58, which is good because it promotes immune cell adhesion and recognition of the tumor cell. But! When CD58 is lost, it then binds to PDL1 and promotes immune cell evasion.
Why nature chose this as a regulatory mechanism is kind of baffling, but exactly the kind of thing that makes cell biology interesting
- xupybd 3y agoOutstanding summary. Thank you very much.
- ccakes 3y agoWarning: no background in science, dumb question inc It seems like the cancer cells are pretty good at evolving to get around our immune system. Is there a reason our immune system doesn’t evolve to outcompete the thing that is killing it?
- pnpnp 3y agoI think it's probably because most skin cancers manifest after reproductive age.
- ElectricalUnion 3y agoIf you have cancer before reproductive age you're selected out of the gene pool; pretty strong survivor bias.
- bglazer 3y agoI should note this is somewhat outside my normal range, so actual experts may disagree. There may be a few reasons. First, as another commenter has noted many cancers manifest late in life, after typical reproductive age. This is decent evidence that our immune system is in fact quite effective at killing cancer already. A rough estimate is that a human body experiences 10^16 cell divisions in a lifetime. Each division is a mutation and therefore cancer opportunity; not to mention the constant barrage of DNA damaging chemicals, radiation, and viruses. The numbers for precancerous mutations repaired (or cells destroyed) over a lifetime would be totally staggering. The flipside of this is that a death from cancer after having kids doesn't reduce the prevalence of your genes in future generations by too much. You already have progeny after all. Humans are social animals and so there's maybe some benefit to having grandma or grandpa around. All that to say that (from an evolutionary perspective) there's not a huge, obvious benefit to having a super good immune system later in life. There's also probably a balance between having an aggressive immune system and auto-immune disease. An over-eager immune system could attack normal cells as well as cancer cells.
- SoftTalker 3y agoYes, also the parent generation eventually dying off confers survival advantages to the younger generation: fewer old folks consuming resources and providing little value in return.
- hughesjj 3y ago
- tommiegannert 3y agoAs a noob, this makes me wonder what happens to a body without PD-L1. Does that make the immune cells themselves exhibit cancerous growth? Does it lead to auto-immune issues?
- folli 3y agoThe immune system is walking a tight rope between being too active and too lenient. PD-L1/PD-1 downregulates immune cells in becoming too active. So removing PD-L1 will cause a number of severe autoimmunity diseases.
- nextaccountic 3y agoHere's a video by Kurzgesagt on evasion by cancer cells https://www.youtube.com/watch?v=zFhYJRqz_xk https://www.youtube.com/watch?v=zFhYJRqz_xk
- DelightOne 3y agoHow can we trust a cell-originating signal without the cancer being able to spoof it? I think there's no hashing for cells yet. Pattern detection comparing cancer with non-cancer block responses? (Trying to wrap my head around this as a noob)
- cabalamat 3y ago> If it senses another (somewhat famous) protein, PD-L1, the immune cell self destructs So why don't pathogens evolve to display PD-L1 on their surfaces, to make immune cells harmless against them? Or do they?
- imdsm 3y agoWhat a horrifying thought
- tux3 3y agoA glance at Wikipedia confirms that some pathogens are aware of PD-L1 and like to mess with proteins that regulate the immune system. Epstein-Barr Virus (EBV), the most common human virus, the herpes that 90% of people have had and a common cause of cancer, apparently has a protein that induces expression of PD-L1. Some other viruses in mice have been observed to do it. What a mess. I love immunology.
- refurb 3y agoPD-L1 already exists in human cells, for cancers leverage it, they just need to overexpress it, which can be a minor genetic change. Pathogens, like bacteria, don't have PD-L1 and it's a very large transmembrane protein. Rather than a small genetic change to over express it, pathogens would need to generate the entire protein by scratch. Possible, but highly unlikely.
- Teever 3y agocouldn't a retrovirus accidentally copy it during replication?
- refurb 3y agoRetroviruses don't have cellular membranes. They could over-express PD-L1 in a cell it infects, but they don't need the cell to live, they want it to lyse and release more viruses (though I guess you could argue it wants it to survive immune attack long enough to do so). Bacteria could potentially do it, but also bacteria cell walls are very different than human. I'm not sure an expressed transmembrane protein could actually be embedded in a bacterial cell wall and still remain functional.