Gene expression profiles of CAR-T cells engineered with chimeric cytokine receptors to induce JAK-STAT signaling
The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is insufficient in most cancers. However, enhancing the antitumor T cell response inevitably increases the risk of cytokine release syndrome associated with monocyte-derived IL-6 secretion. In this study, we developed a chimeric cytokine receptor consisting of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant (insertion of PPCL) (G6/7R). We also generated a modified receptor with the M452L mutation in the IL7R cytoplasmic domain (G6/7R-M452L). CAR-T cells with G6/7R or G6/7R-M452L efficiently absorbed monocyte-derived IL-6 and induced a superior therapeutic response compared to conventional CAR-T cells. Our strategy can be broadly applied to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen. Overall design: Human CD8+ T cells derived from three different healthy donors were retrovirally transduced with an anti-CD19 CAR gene (FMC63-28z) or the CAR gene + G6/7R with or without the M452L mutation. CAR-T cells were then stimulated with the CD19+ B-cell acute lymphoblastic leukemia cell line NALM-6. RNA was collected, and gene expression profiles were analyzed by RNA sequencing.