Thread by @apwiita

Our latest now out @NatureComms! We use cell surface #proteomics to find new #immunotherapy targets and biomarkers of resistance in #myeloma #mssm. Resource + we identify CCR10 as target & develop natural ligand CAR-Ts. Huge effort led by @idferguson
nature.com/articles/s4146…

w/informatics & primary sample analysis led by @bonellpatinoe. Wonderful collaboration with @realjimwells @j_eyquem @iamdrdex and our @ucsfcancer myeloma clinical team @ninashah33 @tombmt133 @myelomawolf @sandywong0211

We initially quantified >1000 membrane spanning proteins across myeloma cells and identified some surprising proteins that most distinguish plasma cells vs. B-cell leukemia, along with canonical markers

We developed a scoring system for surface antigens, integrating proteomics with mRNA-based databases. We find that BCMA is the “winner”, encouraging for the field(!), but several other interesting targets. We focused on CCR10, validating expression on patient plasma cells

And then also using CCR10’s natural ligand, CCL27, to make a first-in-class proof-of-principle CAR-T cell

We further profile the surface of several models of proteasome inhibitor and lenalidomide resistance, identifying surface protein markers of resistance

Intriguingly, short-term drug treatment leads to very different surfaceome alteration than chronic resistance models. We find that lenalidomide specifically increases surface levels of MUC-1, and co-treatment enhances activity of anti-MUC-1 CAR-Ts

Finally, we also develop a modified version of the cell surface capture proteomics protocol, enabling profiling of primary myeloma specimens and verifying signatures we found on cell lines

Excited to get this out! Ian @idferguson started this as a tech in the lab and is now finishing 3rd year of grad school at Stanford. To finish the revisions he split time between Palo Alto and SF for 9 months! #dedication