The Tumor Glyco-Code and Why Immunologists Should Care About it

by Alexandra Cadena

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.

The advances in recombinant glycotransferase have given researchers the necessary tools to make antigens copy structures of tumor glyco-sites, which consequently enhances immunotherapy’s targeting of cancer. The advent of certain glycan therapeutics, such as glycan-based vaccines and glycotransferase inhibitors, have the potential to serve as powerful tools in combination with current immunotherapy drugs, but the important role they may play in the field of immuno-oncology can only be revealed if we continue to take a step back and see the larger picture and the vast forest that is the immune system, which expands well beyond the tumor microenvironment.