Selinexor Reduces the Immunosuppression of Macrophages and Synergizes With CD19 CAR-T Cells Against B-Cell Lymphoma.

CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved high response rates in patients with B-cell lymphoma. However, treatment failure and relapse can be attributable to CAR-T cell dysfunction and the immunosuppression of the tumor microenvironment. Combination therapy emerges as a solution strategy, and selinexor might be a potential candidate. In this study, we first established the ex vivo tumor microenvironment model by coculturing tumor cells and macrophages, followed by coculture with CAR-T cells, and identified that selinexor decreased CAR-T cell exhaustion and enhanced its cytotoxicity. Moreover, selinexor upregulated NGFR expression and boosted CAR-T cell proliferation. The ex vivo and in vivo results showed that selinexor prevented macrophages from polarizing to M2 populations. In the xenograft animal model, the sequential use of selinexor and CAR-T cells significantly reduced the tumor burden compared with selinexor or CAR-T cell monotherapies. In summary, our findings suggest that selinexor mitigates the immunosuppression of macrophages and improves CAR-T cell functionality, and the combination of selinexor and CAR-T cells may be a promising therapeutic strategy for B-cell lymphoma.