Synergistic effects of XPO1 inhibitors combined with CD19 CAR-T cells in TP53-mutated DLBCL

Purpose Diffuse large B-cell lymphoma (DLBCL) is mostly curable by chemotherapy, but p53 mutations limit the therapeutic effect of DLBCL. Although chimeric antigen receptor (CAR) T cells have made revolutionary progress in the treatment of DLBCL, p53 mutations still lead to drug resistance and/or relapse of DLBCL, affecting the prognosis of lymphoma. Therefore, the project aim to explore additional therapeutic strategies to improve the prognosis of DLBCL with p53 mutations. Materials and Methods We investigated the correlation between XPO1 and mut-P53 employing qRT-PCR, WB, CCK8 and flow cytometry. Then, we conduct XPO1 inhibitor (KPT-330) to explore the apoptotic effect on DLBCL. Through the TCGA database, there is a clear correlation between XPO1-related genes and the PI3K-AKT pathway. Finally, the effect of KPT-330 on the killing ability of CAR-T cells was evaluated by CCK8, flow cytometry and ELISA. Results In this study, we showed that XPO1 inhibitor (KPT-330) synergized with CAR-T to reduce the viability of DLBCL cells and enhance the killing effect of CAR-T cells. As expected, KPT-330 combined with CAR-T therapy slowed tumor growth and reduced tumor burden in DLBCL with p53 mutations. Mechanistically, XPO1 inhibitor KPT-330 can cooperate with CAR-T in the treatment of DLBCL by activating the PI3K pathway. Then, in vitro cytotoxicity assays revealed that the KPT-330 combined with CAR-T group significantly enhanced the secretion of effector cytokines IFN-γ, TNF-α, and IL-2, and activated the immune system. Conclusions The XPO1 inhibitor KPT-330 exerts anti-cancer effects through dual mechanisms (stabilizing p53 and inhibiting the PI3K-AKT pathway), providing a molecular basis for DLBCL treatment. We may provide a potential promising combination therapy for the treatment of DLBCL with p53 mutations.