
Highly mutated cancers respond better to immune therapy - pseudolus
https://www.nature.com/articles/d41586-019-00143-8
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apathy
That’s not the important conclusion of the primary article. Highly mutated
cancers _of certain types_ respond better to checkpoint inhibition and so
forth. Melanoma, lung adeno, colorectal with MMR defects, for example. Others
(glioma, high-grade serous ovarian, germ cell for example) don’t seem to get
“hot” immunologically in proportion to their mutation burdens. (And there are
other tumors, serous ovarian hypercalcemic for example, that have a
vanishingly low mutational burden and respond to checkpoint inhibitors
anyways).

The initial results suggested that more mutations == more immune response.
That’s clearly not universal enough to rely upon clinically, although in some
tumor types it’s suitably reliable to stratify clinical trials. In other tumor
types, it looks like we are stuck with trial and error to find good enough
biomarkers for response, as with most drugs.

So while TMB can be useful, it has limitations, and this study (the primary
results, published in _Nature Genetics_ , a related but different journal)
helped clarify where those limitations are. The news & views piece just has
pull quotes.

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yread
I think there were some trials with negative results trying to link just TMB
to immune response or outcome. It's really about problems with MMR genes.

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apathy
Not only, and not always. HGSOC-hypercalcemic is a particularly notable
exception. The idea that it’s always MMR came from Lynch syndrome, but that
doesn’t seem to be universal.

Immunity is complicated, you heard it here first...

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arcticbull
Makes sense, the immune system is for detecting things that aren’t “you” and
killing them, so the more mutated it is the less you it is — the easier it is
to kill. Intuitively, anyways.

I wonder if this is what spontaneous remissions are all about: the cancer
mutates to the point that the immune system picks it up and knocks it out?

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najarvg
The headline is a bit misleading and if you look at the landscape of cancer
immunotherapy research you will see this generalization does not hold at all
i.e. tumor mutational burden is not necessarily a good predictor of response
in all types of tumors. See apathy's response above. W.r.t spontaneous
remission, there have been a few lines of research that would seem to lend
credence to your hypothesis (e.g. - see
[http://www.fevertherapy.eu/](http://www.fevertherapy.eu/)) but it has never
been studies systematically enough to draw any conclusions one way or the
other.

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crb002
This makes sense. Barely mutated cancers are harder to distinguish from cells
with benign mutations.

