Our immune system is a well-orchestrated fort, equipped to fight all kinds of nasty that attack our body. Unfortunately, some attackers come well prepared with weapons for immune evasion and can escape or even confuse our immune system, such as with cancer. In the recent years, we have seen a rise of new potential therapies like immune checkpoint blockade (immunotherapy that can enhance the immune response by preventing tumours from blocking T cells induced immunity). Even though immune checkpoint blockade sounds like the ideal solution, in real life, many patients don’t benefit from it due to the heterogenous nature of cancers. Hence, there is a need to look for other broader ways to enhance anti-cancer immune therapy. One such way could come from the combinational efforts of the University of Basel and Stanford University.
Stanczak and colleagues showed us in a previous research that specific sugar molecules, sialic acid, can have immune suppressive potential. Sialic acids are sugars present in the cell surface glycolipids and glycoproteins (eg. receptors) and play vital roles in cellular communication. These – not so sweet – sugars will convert macrophages into traitors and will thus lower the anti-cancer effect of immunotherapies.
This time, Stanczak and colleagues dive further to explain the need to remove said sugar molecule’s effect in combination with immune checkpoint inhibition to make immunotherapy effective to wider patient populations.
By doing in vivo studies on mice, Stanczak et al. demonstrated that the inability to biosynthesize sialic acid, or pharmacologically blocking sialic acid, can suppress tumour growth as well as prolong survival in different tumour models bearing mice.
Another interesting observation was regarding tumour-associated macrophages (TAMs). TAMs can take up to 50% of the tumour microenvironment and are predominantly pro-tumour and anti-inflammatory. Here they found out that TAMs have a receptor for the sialic acid molecule and by blocking that specific receptor, TAMs can be repolarised into the anti-cancer type macrophage. Such a shift into anti-tumour and pro-inflammatory macrophage phenotype had a tremendous influence in generating cytotoxic CD8+ T cell response (also anti-tumour), finally leading to significant reduction in tumor growth.
Last but not least, blocking the sialic acid molecule alongside immune checkpoint inhibition of PD-1 and CTLA-4 proteins, resulted in tumor rejections in 78% mice. Fascinating!
These findings sound absolutely fantastic, and it will be interesting to see them transferred to human studies, that is if there are similar receptors containing sialic acid residues in humans as in mice. What worries me the most is that systemic blocking of sialic acid can result in a strong blockade in all tissues due to the ubiquitous presence of sialic acid receptors and the requirement of these receptors in various cellular communication and signaling. This ultimately would be fatal. It is questionable how localized this therapy could be. However, there must be a way to overcome these issues and reduce potential toxicity. I, for one, am certainly looking forward to hearing about these in future studies!
Stanczak MA, Rodrigues Mantuano N, Kirchhammer N, Sanin DE, Jacob F, Coelho R, Everest-Dass AV, Wang J, Trefny MP, Monaco G, Bärenwaldt A, Gray MA, Petrone A, Kashyap AS, Glatz K, Kasenda B, Normington K, Broderick J, Peng L, Pearce OMT, Pearce EL, Bertozzi CR, Zippelius A, Läubli H. Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade. Sci Transl Med. 2022 Nov 2;14(669):eabj1270. doi: 10.1126/scitranslmed.abj1270.
Article author: Ines Poljak. Ines is a Ph.D. student at King’s College. She worked at the University of Copenhangen on multiple myeloma bone disease. She worked in several clinical laboratories before committing herself completely to research.
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