Targeting triple-negative breast cancer with combination therapy of EGFR CAR-T cells and CDK7 inhibition
Menée à l'aide de modèles de cancer du sein triple négatif, cette étude met en évidence l'intérêt d'une stratégie thérapeutique combinant un inhibiteur de la kinase CDK7 et des lymphocytes CAR-T ciblant le récepteur EGFR
Epidermal growth factor receptor-targeted chimeric antigen receptor T cells (EGFR CAR-T) are potent and specific in suppressing the growth of triple-negative breast cancer (TNBC) in vitro and in vivo. However, in this study, a subset of mice soon acquired resistance, which limits the potential use of EGFR CAR-T. We aimed to find a way to overcome the observed resistance. Transcriptomic analysis results revealed that EGFR CAR-T treatment induced a set of immunosuppressive genes, presumably through interferon-gamma (IFNγ) signaling, in EGFR CAR-T cell-resistant TNBC tumors. The EGFR CAR-T cell-induced immunosuppressive genes were associated with EGFR CAR-T cell-activated enhancers and were especially sensitive to THZ1, a CDK7 inhibitor we screened out of a panel of small molecules targeting epigenetic modulators. Accordingly, combination therapy with THZ1 and EGFR CAR-T cells suppressed immune resistance, tumor growth, and metastasis in TNBC tumor models, including human MDA-MB-231 cell- and TNBC patient-derived xenografts, and mouse EMT6 cell-derived allografts. Taken together, we demonstrated that transcriptional modulation using epigenetic inhibitors could overcome CAR-T therapy-induced immune resistance, thus providing a therapeutic avenue for treating TNBC in the clinic.