Targeting Wnt/β-catenin signaling enhances the efficacy of anti-CD38 immunotherapy in multiple myeloma.

BACKGROUND: Previous studies have shown that the Wnt/β-catenin signaling pathway is aberrantly activated in multiple myeloma (MM) and regulates the growth of MM cells, while recent studies reported crosstalk between Wnt and STAT3 signaling in various non-MM systems. In addition, it has been shown that STAT3 regulates the expression of CD38, the key target of current antibody therapies in MM. Therefore, we aimed to investigate the impact of inhibiting the Wnt signaling on the efficacy of anti-CD38 immunotherapy.

METHODS: We utilized dnTCF overexpression and β-catenin knockout to inhibit the Wnt signaling. Flow cytometry was used to analyze the expression of CD38. NK92MI-CD16 and CB-derived NK cells were used to conduct ADCC in cell lines and patient-derived MM. A xenograft mouse model was used to evaluate the therapeutic efficacy of inhibiting Wnt signaling in combination with daratumumab in vivo.

RESULTS: We demonstrate that inhibition of Wnt signaling results in reduced STAT3 activity in both MM cell lines and primary MM samples. The suppression of STAT3 activity by Wnt signaling inhibition significantly enhances the expression of CD38, which is a crucial determinant of the clinical response to anti-CD38 treatment, viz. daratumumab. In accordance, targeting of Wnt signaling with the Wnt inhibitor ICG-001 greatly enhanced the anti-MM efficacy of daratumumab in vitro as well as in an in vivo mouse model.

CONCLUSIONS: These findings demonstrated that targeting Wnt signaling enhances the efficacy of daratumumab and provide a strong rationale for combining daratumumab with Wnt-signaling inhibition as a therapeutic strategy in MM.