Resistance to HER2-TCB (T cell bispecfic) and -CAR (chimeric antigen receptor) through JAK2 downmodulation

In this study, we analyzed the transcriptome of parental BT474 and resistant (BT-R) cells to a bispecific antibody (TCB) and chimeric antigen receptor (CAR) targeting HER2. As a result, we observed that resistant cells exhibit a downregulation of the interferon gamma pathway, using gene set enrichment analysis (GSEA) in the hallmark gene sets. We further demonstrated that this deficient response to interferon gamma is the trigger of resistance, and that JAK2, is the component disrupted in resistant cell. As a consequence, JAK2 downmodulation is the cause of resistance to TCBs and CARs. Manuscript: Resistance to HER2-TCB (T cell bispecfic) and -CAR (chimeric antigen receptor) through JAK2 downmodulation. Submitted to Nature Communications (in second round of revision).