In science, it’s so easy…tempting even to be sucked down the
rabbit hole of a particular mechanism or biological pathway only to find that
when you tease out one thread, multiple other avenues of research and discovery
spring forth drawing you further and further into scientific specificity.
Sometimes we get lost. Let’s say we get so caught up looking at a tree that we
fail to see the forest.
I noticed this in a big way when I moved from researching in
a lab that was solely dedicated to uncovering the effects of aberrant
glycosylation in cancer to another lab solely focused on immunotherapy in
combination with radiation. As I write this, I wonder, why do labs “solely”
specialize in one arena?
Yes, I know the obvious answer is for funding purposes, but
maybe the financial structure of how academic research is awarded in this
country is hindering us rather than helping us. Are these “lab niches” in
research stagnating us in that they prevent us from seeing the bigger picture?
Maybe.
We have to specialize in one thing, and then we stay there,
we don’t poke our head out to see what else is out there. One thing’s for sure,
immunologists, or at least the ones I collaborate with, don’t give much thought
to how glycosylation could be affecting the immune system in the fight against
cancer. And I think considering glycosylation in the arena of immuno-oncology
is one good step in the direction of looking at the bigger picture---or entire
forest as it were.
Glycosylation and its by-product, the glycan, play a crucial
role in many cellular processes. Aberrant glycan structures and mutations of
the glycosylation pathway have been intricately linked with the development of
cancer and more recently with cancer’s ability to escape the innate immune
system. Glycosylation’s interaction with the immune system can promote tumor
deviation through endogenous lectins, mutated, sialic acid domains and more….so
why not move to combine some of our top of the line immune drugs with
glycotransferase inhibitors?
This may even be the answer as to why some patients don’t
respond to certain lines of immunotherapy treatment. In 2016, Li et al.
presented findings in Nature Communications that found immunosuppression
activity of PD-L1 was highly regulated by N-linked glycosylation. The Contessa
lab group at Yale developed a small molecule inhibitor called NGI-1, which
selectively inhibits N-linked glycosylation in only malignant cells. Fruitful
collaboration? Possibly.
The tumor glyco-code may hold another secret for
immunologists to unlock another avenue of tumor immune escape. There are some
groups that are already starting to take note and develop glycan-based CAR T
cells. In fact, the Carl June lab recently developed a Tn-MUC-specific CAR T
cell, which has been effective in eliminating leukemia and pancreatic cancer in
mice.
