Pillar 1 - FTO (new thread), page-284

Awesome study released yesterday1 (3/3/21) that I was going to talk about on Sunday (pending my girlfriends permission, of course), but I just couldn’t help myself as it is another article that suggests FTO overexpression influences anti-PD-1/PD-L1 therapies. This is from my understanding and is speculative, although I think my understanding and extrapolation is reasonable.

The article was investigating the mRNA regulatory proteins (like FTO) associated with tumor-associated macrophages. It had a specific focus on Mettl3, which is known as a methylator (adds a methyl group to adenosine to make it N6-methyladenosine. Mettl3 is also referred to as a writer. FTO is known as an eraser (it does the opposite job - removes a methyl group).

The studies key findings were that: 1) ablation (removal) of Mettle3 promotes tumor growth and metastasis in vivo (living creatures); 2) Mettl3 deficient mice had increased M1/M2-like tumor-associated macrophage and regulatory T cell infiltration into tumors; 3) that loss of Mettl3 led to increased tumor growth and metastasis; and 4) the therapeutic efficacy of PD-1 checkpoint blockade is attenuated (reduced effect) in Mettl3-deficient mice.

I understand that this article is referring to METTL3, but here is where it gets interesting. Using the figure below as an example - inhibition, deficiency, or ablation of METTL3 would lead to an accumulation of Adenosine (the left side of the figure below).

The important thing to recognise is that this situation has created a similar circumstance to FTO overexpression. You will see in the figure below that FTO overexpression (without inhibition of METTL3) would lead to an overproduction of adenosine similar to inhibition of METTL3.

Also, Dr. T has stated previously that mRNA modification in mice is very similar to humans - in fact, it hasn’t changed for millions of years.

So, I find it reasonable to assume that FTO overexpression may have led to similar findings reported in this paper, which, therefore, if true, would implicate that FTO overexpression increases tumor growth and metastasis and impedes the therapeutic efficacy of anti-PD1 therapies. This conclusion is supported by recent research that has investigated the role of FTO in anti-PD1 therapies,2-4 where FTO overexpression was found to decrease response to anti-PD1/PD-L1 therapiesand FTO inhibition increased sensitivity.2-4 At the very least, this study indicates that increased concentration of adenosine leads to an unfavourable prognosis that could be modified by pharmacological intervention.

https://www.nature.com/articles/s41467-021-21514-8.pdf

https://www.researchgate.net/publication/342113813_Targeting_FTO_Suppresses_Cancer_Stem_Cell_Maintenance_and_Immune_Evasion

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136921/

https://www.nature.com/articles/s41467-019-10669-0