Friday, October 20, 2023

Systematic discovery of neoepitope–HLA pairs!


Holy. shit. I think Genentech just drew a line in the sand and said that amateur hour is coming to a close for HLA neo-antigen discovery....

The amount of work in this is crazy. And the level of validation is extraordinary. Switching the top figure for the post to a protein I know pretty well. Not Megan Rigby well, but I acknowledge her in a lot of my papers for very good reasons. 

We know without any doubt at all that KRAS peptides makes it to the HLA expression system. Bert Vogelstein has 5 very good papers on this and has a brand new aggressive spinout company full of badasses who are working on exploiting this.

Rose's team exploited this in their validation by constructing cell lines where they can induce mutant KRAS expression! Those bar charts above show the specificity of their their toolkit! They can induce the system and measure the correct antigen production with absolute(?) quantification. 

This is important because...? If you've got one copy of a neo-antigen on the surface of a cell, that isn't enough to use to target it for destruction through CAR-T or whatever system. There is a threshold - I think of as almost the immune system false discovery rate. 1 copy doesn't trigger DESTROY THIS CELL. But 50 copies almost certainly does. 

I started with the validation that this method works. What you want to read it for is - that they used the validated system to identify a crapload of novel neoantigens. 

Seriously seriously cool work. 

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