Reprogramming Macrophages: The Key to Turning the Immune System Against Cancer

Harsha N, a student at Detroit Country Day School, dives deep into the complex world of our immune system, and discovers a surprising twist: the very cells meant to protect us from diseases can actually aid in cancer growth. Through his research on macrophages, he reveals how these immune cells can be reprogrammed in the tumor microenvironment to become tumor-assisted macrophages, or TAMs, which support tumor development instead of fighting it. Harsha emphasizes that this adaptability of macrophages opens up potential avenues for innovative cancer therapies, suggesting that if we can understand how to reverse their programming, we could shift the immune response back in our favor. He also reflects on the broader implications of cellular flexibility and communication, prompting us to consider what other systems in our bodies might be more malleable than we previously thought. This episode invites listeners to explore the intricate connections between our biology and cancer, highlighting the need for a nuanced understanding of these interactions.

Episode Transcript

(00:07):
Hello, my name is HarshaNarayan and I've always been fascinated
by the hidden systems insideour bodies.
The ones that protect us, healus, and sometimes surprise us.
I've been doing research onthe immune system, especially a powerful
cell called the macrophage.
I hope to pursue a career inmedicine or biomedical research.
And what drew me in was theway science can uncover stories we

(00:27):
never first expected.
Now imagine this.
The very cells designed toprotect you from disease.
The cells of your immunesystem are actually helping cancer
grow.
I've done some research andwork on a particular kind of immune
cell called the macrophage.
And would like to furtherexplore them.
Normally, these cells are yourbody's cleanup crew.
They eat bacteria, clear outdead cells and keep inflammation

(00:49):
under control.
But in the tumormicroenvironment, they don't fight.
They switch sides.
In cancer, macrophages can bereprogrammed into what's called a
tumor assisted macrophage or tam.
Instead of attacking thetumor, they help it grow.
They build blood vessels for it.
They suppress the immune system.
Or they clean up the mess thatcancer leaves behind so it can more

(01:10):
easily spread throughout your body.
But here's the hopeful.
These cells aren't locked intothat role.
They're adaptable.
Which means if we understandhow they are reprogrammed, we might
be able to reverse it.
So Then what are tams?
Macrophages can exist on a spectrum.
The M1 are the fighters.
They are pro inflammatory andanti tumor.

(01:33):
While the M2 are the healers.
They are anti inflammatory andtissue repairing.
TAMs resemble more of the M2 macrophages.
The tumors hijack theirhealing properties and turn them
into bodyguards.
They release many differenttypes of anti inflammatory signals.
They even express PD L1, whichsucks down the T cells that could

(01:54):
kill the tumor.
One of the ways tems do thisis by releasing little messages called
exosomes.
Exosomes are like little nano mailboxes.
The tiny vesicles carryproteins, RNA and different surface
markers.
TEM derived exosomes carry PDL1 and deliver it to other cells.
This delivery amplifies theimmunosuppressive effect across the

(02:17):
tumor.
Now, to make exosomes youfirst need endosomes which are little
membrane bound bubbles insidethe cell.
The acidity inside theseendosomes is crucial as it determines
whether they send their cargoto the lysosome where it is destroyed
or to the plasma membrane tobe released out of the cell as exosomes.
There is a protein called NHE9that controls this phase and it works

(02:40):
Like a proton leak, itneutralizes the inside of the endosome.
So when NAG9 is upregulated,endosomes become more basic or alkaline.
This promotes exosome releaseand blocks their degradation.
In a recent study, overexpressing Nag9 in cancer cells increased
exosome production by over 140%.
The exosomes they releasedcarried more PD L1, and they were

(03:03):
better at suppressing CD8 T cells.
And in mouse models, reducingNHE9 made tumors more vulnerable
to anti PD1 immunotherapy,which is good.
Now, why does this matter?
It matters because it showshow deeply cancer can manipulate
our own biology.
Tems make up a huge portion ofthe cells in any given solid tumor.

(03:24):
So if we can control theirbehavior, for example, if we can
lower exosome production orreprogram the tems back into regular
M1 type macrophages, we don'tjust slow down the tumor.
We turn the immune system backon our side.
Now, when I first learned thatthe immune system could betray us,
I was shocked.
I'd always seen it more as ablack and white thing.

(03:44):
The immune cells are good forus, and the cancer is bad.
But while studying this, ithas made me realize that biology
is much more messy.
It's not about just good andbad, black and white.
It's about more complex,interconnected content with different
signals and in differentenvironments that all affect the
outcome.
So now, here's my question.
If macrophages can bereprogrammed, what else in the body

(04:05):
is more flexible than we thought?
Could we learn to flipswitches in different pathways in
different cells?
Could we create therapies thatdon't just attack the tumors, but
rewire the entire ecosystem?
That's the power ofunderstanding cell communication.
It's not just a series ofsignals, but a language that we're
beginning to speak more and more.
Now, if we listen closelyenough, we might not just treat the
disease more effectively, wemight change the way that we think

(04:27):
about healing altogether than SA.