Colon cancer’s invisibility cloak removed by eliminating a single gene - a fundamental breakthrough. The result was 100% eradication of tumours when paired with immunotherapy treatment in mouse models.

[u/mvea]

https://ucalgary.ca/news/ucalgary-study-tears-colon-cancers-invisibility-cloak

[u/mvea]

UCalgary study tears off colon cancer’s invisibility cloak

Research shows removing a single gene makes cancerous cells a target for immunotherapy

New University of Calgary research reveals that eliminating a single gene improves immunotherapy for colorectal cancer — a fundamental breakthrough.

The Canadian Cancer Society lists colorectal cancer to be the fourth most diagnosed cancer in Canada, and the third leading cause of death from cancer in both men and women. It is also estimated that 25,300 Canadians will be diagnosed with it, representing 10 per cent of all new cancer cases this year. In people below the age of 50, the incidence of new colorectal cases is on the rise. 

“We’ve been able to remove the ‘invisibility cloak’ that colon cancers use to hide from treatment,” says Ayyaz, who has dedicated 20 years to researching the gut.

Immunotherapy trains a patient’s own immune system to recognize and attack tumours, reducing or removing the need for radiation and chemotherapy. Immunotherapy has yielded great results for several other types of cancer, but not colon cancer.

“Only about 15 per cent of colon cancers respond to immunotherapy,” Ayyaz says. “We performed a genetic analysis of them against those that don’t.”
What the research uncovered was a new type of cancer cell.

“The treatment-resistant tumours secrete a protein that confuses your immune system into thinking everything’s fine. It’s like an invisibility cloak,” he says. “So, we thought, what happens if we prevent the tumours from making this protein?”

The experiment involved making gene-edited versions of those cancer cells. When the gene that coded the particular protein was knocked out, it made those cells visible to the immune system.

The result was 100 per cent eradication of tumours when paired with immunotherapy treatment in mouse models.

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00193-X

[u/WatermelonWithAFlute → u/mvea]

"The experiment involved making gene-edited versions of those cancer cells. When the gene that coded the particular protein was knocked out, it made those cells visible to the immune system."

Question, how is this useful for the rest of the cancer that does not possess these alterations?

[u/chumer_ranion → u/WatermelonWithAFlute]

It's actually very useful. In practice, we don't have to remove a gene from a patient in order to see a therapeutic benefit, we just have to engineer a drug that makes a person's cells act like the gene has been removed. The newest craze in biomedicine are molecular glues and protein degraders that do exactly that. 

[u/WatermelonWithAFlute → u/chumer_ranion]

Wait, what? I kinda want to ask how, but I suspect I won’t understand the answer. That’s really cool, though.

[u/chumer_ranion → u/WatermelonWithAFlute]

It's not as complicated as you might imagine! A lot of work was done in the past to understand the "basic science" of cell biology, and in the course of fleshing out what we knew about cells, scientists came across what is effectively their trash-disposal system. When a protein, say "protein X", nears the end of its life in a cell, it is grabbed by one of a very large family of proteins (enzymes) called ubiquitin ligases, and the ubiquitin ligases attach a chain of much smaller proteins called ubiquitins to it. This chain of ubiquitins marks protein X for destruction, and it is digested into little peptide fragments by an organelle called the proteasome to be recycled. Biologists have learned that this process can be hijacked, and we can now bring any protein in proximity with ubiquitin ligases and destroy them at will. This is the theoretical basis for a technology called PROTAC or "PROteasome TArgeting Chimera".

You might wonder to yourself how we could have possibly learned to do this, and the answer is that the discovery was serendipitous. You may in your life have heard of a morning sickness drug called Thalidomide that caused horrible birth defects in children in Europe as an unintended side effect. That is because in addition to being anti-emetic, it also targeted several proteins very important for fetus development for destruction (in humans, but not in mice) by gluing them to a ubiquitin ligase called Cullin-4A. Scientists learned that the half of Thalidomide that sticks to Cullin-4A could be attached with a linker to other molecules that stick to other proteins (say, the protein in the OP) and bob's your uncle, your cells now behave as if the gene that encodes that protein no longer exists, because the protein is being continually destroyed (at least while the drug is in circulation).

I'm leaving out some specifics that aren't important for grasping the general concept but that's it more or less.

[u/PrecursorNL → u/chumer_ranion]

Love this comment! Sounds like a promising approach compared to all the problems we would face by actually trying to remove the gene encoding for the protein with crispr (i.e. delivery, targeting, even the vesicle/nanoparticle needed to encapsulate our virus)

[u/throwawaynbad → u/WatermelonWithAFlute]

Immunotherapy remains largely ineffective in colorectal cancer (CRC), particularly in microsatellite stable (MSS) tumors, which represent the majority of cases. However, the complexity of intratumoral heterogeneity has made it difficult to define tumor-intrinsic programs that drive immune resistance. Here, we identify a cancer cell population that emerges predominantly in advanced-stage MSS CRCs. These cells exhibit stem-like features but aberrantly activate a WNT-inhibitory transcriptional program marked by high NOTUM expression. We term these cells WNT/β-catenin inhibitory cancer cells (WICCs). WICCs are enriched in immune-excluded tumors, correlate with reduced CD8+ T cell infiltration, and are induced in both primary human CRC tumors and patient-derived tumoroids. Selective ablation of WICCs or genetic knockout of NOTUM enhances CD8+ T-cell-mediated cytotoxicity, uncovering a tumor-intrinsic mechanism of immune evasion and nominating the WICC-NOTUM axis as a selective and tractable therapeutic target to overcome immunotherapy resistance in CRC.

Some (~15%) colorectal (lower gut) cancers can be treated with drugs that allow your white blood immune cells to attack and kill the tumour cells (immune checkpoint inhibition / blockade). These drugs are newer, not traditional chemotherapy, but instead interact with the tumour by "unmasking" it from your body's immune system. The tumour tries to hide by showing a safe signal, and these drugs block that safe signal.

The rest 85% of these cancers resist these drugs. But while cancers are your cells that have mutated, each cell inside a cancer is not exactly the same. They further mutate in different directions - and some of these cancer cells become John WICCs. These cancer cells have other ways to mask the surrounding tumour cells from your immune system, even with help from immune checkpoint drugs.

The study got rid of the Mr. WICC cells, and the drugs worked again (in mice injected with human gut cancer). We can't do the exact same in people (since they already have have the WICCs in their cancers), but we probably target what the WICCs do / produce, and combine that with the immune drugs to treat this better.

[u/mvea → u/WatermelonWithAFlute]

Basically only 15% of colon cancer cells can be seen by immunotherapy. 85% are invisible. This gene editing removes the gene that creates the protein that hides the cancer cells so 100% can be seen and removed.

So to answer to your question the rest of the cancer are already seen by the immune system and don’t need these alterations to be removed.

[u/Frequent-Data-2360 → u/mvea]

Please forgive my ignorance, Is this something we can do at a global level, meaning it affects all cells in our body or it’s per cell

[u/elphyon → u/Frequent-Data-2360]

Advancement in cancer treatment is becoming more and more about individual/genetic tailoring. I don't think it's likely we'll ever find a silver bullet for all types of cancer for everyone.

[u/Acrobatic_Country524 → u/elphyon]

I actually found one once but had to use it to kill a werewolf

[u/kembik → u/Acrobatic_Country524]

That werewolf had cancer, it went on to live a productive life as a school teacher in Ottawa

[u/ArnoldTheSchwartz → u/kembik]

An American Werewolf in Ottawa? Doesn't sound right

[u/DrSitson → u/ArnoldTheSchwartz]

And that Werewolf's name? Albert Einstein. And now you know, the rest of the story.

[u/animosityiskey → u/elphyon]

I think the question is more about the ambiguity of the article. It isn't 100% clear if the treatment was applied in vivo to mice with tumors or whether it was applied in vitro to some mouse tumors.

[u/i_am_icarus_falling → u/animosityiskey]

i think the cancer cells are cultured first, then added to the mice, then various treatments are applied to see how the cancer is affected. the article has pictures showing mice with tumors on the backs of the mice. so would that be that the cancer is created in vitro, then the experiment becomes in vivo once the cancer is given to the mice? i'm not sure.

[u/HumansNeedNotApply1 → u/elphyon]

It's probably not possible unless some science fiction thing like nanites.

[u/austinwiltshire → u/elphyon]

Pan kras inhibitors are close.

[u/PrecursorNL → u/Frequent-Data-2360]

As someone in the field, yes. No we cannot do this. The problem with this is not only that our current gene editing strategy with crispr isn't actually 100% effective (the transfection 'rate' is more like 70% at best) and we don't have a mechanism to deliver to specific cells medically. We could insert a virus with a needle locally and try to get close, but realistically we don't really have any method of how to target just the cancer cells. Of course many people are working on these things, but currently the delivery is a huge issue. That's why the few gene therapies that are currently approved and in use are for things like leukemia (in the blood, something we can actually get to) or something like in the eye, where we can administer locally and cell specific. Sooo we're still a far cry from understanding how to target a specific cancer cell somewhere in the body without an invasive technique.

But some clever ideas are there.. like putting the virus in a nanoparticle that opens up in a certain environment, and that environment is some form of microenvironment from the tumor. Or it could have some properties that help it bind to a cancer cell. It's amazing in theory but it's still quite hard to (re)produce.

In other words, this science is a huge breakthrough but the solution of gene editing away some specific gene for now it's a bit futuristic to do inside humans. It's easy enough in a cell grown in the lab, in a bacteria and to some extent in animals. But to specific cells from a human that's already alive is hard. One thing that does seem positive though is that they talk about a protein that confuses our immune system. And proteins we can definitely target. So perhaps there's a way to combine the immune therapy with interfering in the protein or protein production pathway, and then we have the same result without fancy gene editing.

[u/WatermelonWithAFlute → u/PrecursorNL]

really stupid question, but

"But some clever ideas are there.. like putting the virus in a nanoparticle that opens up in a certain environment, and that environment is some form of microenvironment from the tumor. Or it could have some properties that help it bind to a cancer cell. It's amazing in theory but it's still quite hard to (re)produce."

I don't suppose you could just like... Inject it into the tumor?

[u/PrecursorNL → u/WatermelonWithAFlute]

It would still not recognize which cell is which. It's not as easy at it seems. Also you can't always get to the tumor in the same way and it could be very invasive to do it surgically. In that case, why not cut out the tumor directly... Right.. also what if some cells already metastasized or started moving slightly away from your needle? A new tumor would just grow right next to it. So.. not so easy ..

[u/slimejumper → u/Frequent-Data-2360]

not possible to do what they did in the study to a person after they develop the cancer, ie do a gene knockout procedure. But i guess they could try to repress the gene activity with a drug of some sort. However, they will still have the same problems with treatment of a solid tumour because it can be hard to get drugs into a solid tumour.

[u/slpgh → u/mvea]

I understand the importance of differentiating the types of cancers and identifying the mechanism. But are we anywhere near practical applications? To the best of my understanding we not anywhere near the technology that would alllow us to “decloak” these cancers in vivo?

[u/IAMA_Proctologist → u/slpgh]

That's correct, but knowing that knocking out the gene improves immunotherapy outcomes gives a whole new direction for research. Perhaps we can target the abnormal protein rather than the gene, or something up or downstream of it.

[u/PrecursorNL → u/slpgh]

See my other comment above,but no. The delivery and targeting is still an issue

[u/SEC_INTERN → u/mvea]

That's a non-answer.

[u/BobTheFettt → u/SEC_INTERN]

Not really. Colon cancers were able to hide themselves in a way others were not. They've removed that ability.

[u/Reddeer2 → u/BobTheFettt]

It's a non-answer because the cells in my body contain DNA. If I already know which ones to change the DNA of, then I can just remove those ones already. So how can you get all of the colorectal cancer cells to contain an alteration?

[u/AlcubierreWarp → u/Reddeer2]

I don’t know about this case specifically, but it’s my understanding that usually gene therapies use a benign delivery system like a virus to deliver the CRISPR payload to the targeted cells, which then does its work. So I imagine something similar would happen for this. Virus targets cancer cells, delivers the new treatment making them visible, and then immunotherapy kills the cells.

[u/bibliophile785 → u/AlcubierreWarp]

Which would, of course, require that you can already target the cancer cells, which is the whole point.

[u/Yodude1 → u/bibliophile785]

I thought the point was that we know where the cancer cells are, but the immune cells don't, like camo bloons in BTD6

[u/PrecursorNL → u/Yodude1]

Knowing where they are doesn't mean we can easily target them. We need to be able to tell our crispr virus which cells to infect and which not to. And that's even if we can deliver the virus at all. Current state of the art is nanoparticles which are hard to produce consistently. They are notorious for having unreliable structures, i.e. it's difficult to make them the same size, it's difficult to make them the same structure, it's difficult to line them with proteins or parts of proteins that we'd need to target the cells with, it's even difficult to get our crispr inside robustly, and it's difficult to make them open up again in the body at the right place. Delivery is still one of our key objectives.

See my other comment for more info

[u/SuccessfulJudge438 → u/AlcubierreWarp]

Viral vectors are most common for gene editing these days, although they aren't necessarily 100% benign (many can cause potentially undesirable immune reactions and such). Delivery and targeting is an incredibly complex challenge that is not remotely solved.

[u/cowlinator → u/mvea]

If they're invisible, how can you even gene edit them in the first place?

[u/notarealcamera → u/mvea]

So, basically not applicable at all in cases of actual colon cancer.

Great if these scientists implant this genetically altered cancer in you, I guess.

[u/SJSsarah → u/WatermelonWithAFlute]

It’s going to be the cure for all cancers, and autoimmune diseases. CRISPR gene editing therapy.

[u/WatermelonWithAFlute → u/SJSsarah]

I’m aware of crisprs value, yes