[apathy]

Also worth noting: this is further evidence that cancer, like many other diseases, is in part an immune disease.

When central tolerance is too lax, tumor cells can more easily survive a trip through the bloodstream to seed metastasis (the eventual cause of nearly all cancer deaths, aside from treatment sequelae and thrombosis).

By contrast, if central tolerance is overly tight, then you see autoimmune diseases (severe aplastic anemia is a classic example) where the immune system wipes out the competition from healthy progenitors, and mutant clones better able to survive the onslaught seed cancers. This is one reason why both immunosuppressive therapies and immunostimulatory agents can both increase cancer risk.

It’s also worth noting just how different the mutational profiles of pediatric tumors are versus adults. To grossly oversimplify, peds tumors tend to carry mutations (typically gene fusions, amplifications, or deletions) that confer a developmental-stage-specific advantage in proliferation, such that no normal progenitor could ever hope to keep up. By contrast, the most frequently observed point mutations in adult cancer (to TP53, in particular, although DNMT3A in leukemia is another example) confer stress resistance to the mutant clones. They are nearly absent from tumors seen in children. Even Li-Fraumeni syndrome, where people carry deleterious TP53 variants inherited from their parents, does not begin to show a huge risk differential until adolescence. So there are evolutionary, developmental, and immune differences that shape the genesis, selection, and growth of different tumors in different age groups, and tend to indicate different treatment.

The standard chemo regimens for pediatric ALL (acute lymphoblastic leukemia, the most common cancer in kids) would kill many adults, and despite over 90% cure rates in kids, far less than half of adults with the “same” disease will survive it. (In quotes, because as with every other tumor that spans the full range of age groups, the drivers in adults are different from those in kids for almost all instances).

Similarly, immune checkpoint inhibitors can generate miraculous responses in adults tumors, though these are seldom seen in pediatric patients. With the benefit of hindsight, it’s more obvious why this is so (the random accumulation of mutations over decades in adult tumors is more likely to generate immune-recognized non-self proteins), but it took a long, long time to get here. (Look up “Cooley’s Toxins” if you think immunotherapy is new :-/)

I still find the fields fascinating, despite having enough ghosts on my conscience to stock a mausoleum. Cancer is part of our evolutionary heritage; the best we can do in adults is usually try to control its spread and cut out enough of it for the immune system to mop up the rest. Kids are different, but that’s another story for another time. It’s a great period in history to be working on understanding these things and they interact.

[rolltiide]

> Also worth noting: this is further evidence that cancer, like many other diseases, is in part an immune disease.

I think about that sometimes but from the lens that perhaps there is an additional state that cancerous cells are preventing from occurring.

"We cured cancer, but then the worst appeared"

[apathy]

Dubious — cellular senescence (whether proliferation- or oncogene-induced) is the usual failsafe for avoiding proliferation of damaged cells. It relies heavily upon TP53, RB1, and CDKN2A, all of which are routinely deleted in tumors. When anti-aging researchers refer to senolytic drugs, usually they’re referring to drugs that clear senescent cells.

Oddly, the drugs tend to clear out tumor cells in many cases, as senescence bypass is a critical step in carcinogenesis.

Not oddly, the inflammatory paracrine (secreted) profile of senescent cells tends to engage the immune system in clearing them out. Immunosenescence gets in the way of this and also of clearing precancerous cells, hence it is a risk factor for both age-related frailty and cancer.