Gene Splicing Revealed as Key Factor in Blood Cancer Immunotherapy Resistance

Immunotherapies targeting the CD20 antigen have transformed the treatment landscape for various blood cancers and hematologic disorders, but challenges remain. Now, a new study from researchers at Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania has unveiled yet another hurdle: gene splicing within cells, leading to significant changes in CD20 protein levels and rendering these therapies ineffective. Published in Blood, their findings also challenge previous assumptions by suggesting that patients with very low CD20 levels may still respond to CAR-T therapy.

CD20, a cell-surface protein crucial for B cell responses, becomes an ideal target for monoclonal antibody therapies in treating B-cell lymphomas. Despite the success of anti-CD20 therapies, some patients develop resistance due to a loss of the CD20 antigen, disrupting the intended target. The new study, led by senior author Andrei Thomas-Tikhonenko, identifies a mechanism where certain mRNA isoforms responsible for CD20 production undergo splicing, hindering effective translation of the protein.

The researchers focused on the MS4A1 gene, revealing four variants, with V3 being efficiently translated into CD20. In contrast, V1 struggled to recruit ribosomes, making monoclonal antibodies less effective. Surprisingly, the study showed that CAR T-cells remained effective against both V3- and V1-expressing cells, challenging previous beliefs about the therapy's limitations in malignancies with reduced CD20 levels.

“If a patient has relapsed because CD20 levels are downregulated, CAR T-cell therapy may still be an option, as it requires a lower threshold of the protein in order to be effective,” said first study author Zhiwei Ang. “These findings may help clinical staff offer more precise options when treating these hematologic malignancies.”