Malignant melanoma deploys elegant molecular mechanism to evade immune responses
cancer.columbia.edu
cancer.columbia.edu
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
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?
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.
I'm completely talking out of my ass here, but I suspect systems will tend towards rent seeking/"cheating"/maintaining a status quo/really, just "overfitting" to the environment by making the ecosystem around them dependent on them.
Death ensures resiliency and progress. If we ever actually achieve some form of (pseudo-)immortality, i'd hope that we introduce an "afterlife" which removes the post-mortal from "living" society/ecosystems after s certain point. at most, living society should be able to inspect & affect the post-living system (afterlife), but the post living system should be airgapped from being able to (at least, directly) affect the living one at all. that said, i'd be wary about indirect affects. to die is to not influence. i'm still influenced by the memory/simulacrum of my grand mother who raised me until middle school. thats some degree of affect on my ecosystem, but it isnt what i would call direct.
i suppose there need not be a singular timeout or ecosystem a system is depolyed to, so long as it converges to zero. Heck, not even monotonically nor with a consistent cohort of systems.
Like the Undying Lands in LOTR?
I feel like this hypothetical scenario is contradictory (and, supposing there was engineering behind both this life and an afterlife, is an argument for keeping the two isolated). Data is code, so data collected from the afterlife is potential for "remote execution from the afterlife" (not that humans are computers, but for example traditionalists who were able to directly study the long-dead would act differently than if they had to piece tradition together from scraps of documents - particularly, it would freeze traditions/memes rather than letting them evolve) and therefore death losing its role as the cessation of influence.
This is also why institutions should have a lifetime. Corporations, government entities, all the things that don't have a natural life length really ought to.
As a parent living by my in-laws, I can assure you that, far from providing "little value", raising children without support from grandparents would be severely more difficult. Personally, I see generations trying to be independent of one another as a large factor in making modern childrearing increasing difficult.
And this is aside from the knowledge, and labor that would have been so vital in former times. The old woman spinning and knitting is a historical trope, but when you have to hand make all of your textiles, she becomes quite useful indeed.
This is the key. I’ve had an immunologist explain to me (over a bottle of wine, so my recollection is hazy) that our immune system is actually very very aggressive already and tuned within a few percentage points of being problematic.
Also, the evolution of cancer cells to get around an immune system happens on a completely different timescale to the selective pressures for the human immune system to avoid cancer (days vs decades).
You really don't want your immune system to move fast and break things.
Frankly it's amazing it works at all - not only does the immune system have to be able to react to stuff it's never seen before - it needs to be able to distinguish between self and non-self - and self is pretty damn complex.
So to make an analogy - cancers like a bunch of terrorists in a busy shopping centre and the immune system is the government response. Only one side has to worry about bystanders.
PD-L1/PD-1 downregulates immune cells in becoming too active. So removing PD-L1 will cause a number of severe autoimmunity diseases.
Pattern detection comparing cancer with non-cancer block responses?
(Trying to wrap my head around this as a noob)
So why don't pathogens evolve to display PD-L1 on their surfaces, to make immune cells harmless against them? Or do they?
What a mess. I love immunology.
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.
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.
The adaptive pressure is your body constantly detecting and killing pre-cancerous cells. Eventually some will get a lucky mutation and slip through.
A human cell can never survive on its own. But there might have been a time when cells could have benefited from "pulling the escape hatch" and taking their chances instead of continuing cooperation within a damaged early multicellular organism.
The only problem is that these individually minded (cancer) cells have every ability of your healthy cells and have basically stopped caring about the greater whole and care about themselves. Then they evolve at a micro level for their survival to fend off chemo, immune system, radiation etc. All it takes is one adapted/surviving cell to come back strong.
The sophisticated mechanisms for evasion exist because they have all the methods of evading your immune system that healthy multicellular organisms need to function and they multiply and increase their mutation rate to try new methods to survive and thrive.
I view cancer cells as single cells to understand their behavior with the adaptations of all the healthy cells returning to their “baser instincts”.
Source: Caretaker of a cancer patient and former cell bio major
PS: Take all the above with a grain of salt
Fuck Cancer
I'm not sure why there was so much talk about 'nanomachines' some years ago when there are literally millions of pre-existing examples that are so vastly more sophisticated.
> Oh, I agree, imagine a "grey goo" apocalypse, where uncontrolled and hyper-aggressive nanotechnology spreads everywhere in a unceasing orgy of consumption and replication. Mutating according to its own unknowable logic, it eventually it covers the land in an inhospitable blanket of massive crawling megastructures and inscrutable malign hive-minds!
> ... Oh, wait, that happened -- It's us. :P
When you talk to other people who don't have kids, they always make sure to let you know they don't.
Different primary tumors (eg Prostate, breast, lung) have preferred sets of metastasis sites that are not always explained by where they get stuck due to getting into the blood supply. Even getting into the blood supply requires functions of degrading extra cellular matrix, evading immune surveillance, getting out of blood vessels and “setting up camp” at the news destination, and those requirements can be cancer and/or met site preferential.
Much of the immune suppression mechanisms are actually regulated systems normal cells use to prevent runaway inflammation. Cancer finds that function and highjacks it to “hide”. Conversely (to further illustrate complexity), some cancers use aspects inflammation as ”fuel” to drive tumor growth especially early in the cancer. I do agree- it is all truly fascinating.with that said: Fu*k cancer.
Isn't this just selection bias on a grand scale? You're looking at a specimen where the parts happened to end up arranged in a way that allows it to exhibit these properties that seem like coordination, while not paying much attention to the quintillions of specimens that did not.
And I’d also point out that these functions that are “sought after” by cancer are not all de novo, some things are complex functions that encoded for use by other normal cells at a other times and places in development of the organism. Some key mutations that enable the use of those functions by the cancer are crucial moments cancer development. Also many key mutations are loss of functions, which are often easier to accumulate. A example of genetic Losses of function is losing “contact inhibition” where normal cells stop growing when they get neighbors. Cancer cells loose this inhibition and just continue growing. This alone would require a suite of mutations. Another comment in the thread talks about cancer evolution and the good of the organism not making sense. Cancer doesn’t care about the organism. The organism has evolved many layers of checks and balances that can work for decades, but throw in time and poisons like smoking, UV damage, and there will be loopholes found. Cancer is persistent and has the entire genome of functions to turn on and off in various ways. Seriously Fu*k cancer.
"Whoever created the mosquito's eye ,created the sun. Whoever ordered the flea' stomach, ordered the solar system." from Quran's light
The death of a cancer's host body is like our equivalent of our star dying, and I guess our equivalent of interplanetary colonization would be a hypothetical cancer's ability to jump between hosts.
Cancer can and does bring about the death of its host.
(One might argue that both humans and other life forms have the potential and/or demonstrated capability to transform their own ecosystem beyond its viability to continue to sustain and support them, with both the present anthropogenic greenhouse-gas-based global warming and the Great Oxygenation Event and subsequent Snowball Earth serving as examples.)
That said, I understand your analogy.
There are virally- and clonally-transmitted or otherwise contagious cancers:
<https://en.wikipedia.org/wiki/Clonally_transmissible_cancer>
(These are rare and seldom found in humans.)
The thing with evolution is that it is random. So sometimes it really doesn’t make any logical sense.
Nothing intelligent is happening. Zero-foresight self-amplifying systems that will inevitably crash out will simply amplify themselves to that point, then cease. Applications to areas outside of oncology are an exercise for the reader.
"Anti-PD-1 and Novel Combinations in the Treatment of Melanoma—An Update"
As it happens I can spot that the linked paper is already out of date as I know at least one is the trials has been cancelled, because I was on it.
https://www.sciencedirect.com/science/article/abs/pii/S15356...
"Malignant melanoma manipulates marvellous molecular mechanism, managing masked malevolence"
Sorry, it's been a rough day.
I would rather see a word such as grotesque or monstrous used, or a phrase such as brutally efficient. That indicates a similar type of imposing magnitude, but also a lack or distortion of beauty.
This is indeed very common in the real world, and often talked about in one way or another on HN. So much so that the parent almost certainly has seen multiple examples after nearly 15000 comments and 13 years on HN.
The outcome not so much.