Immune-modulatory effects of Spindlin-1 inhibitors.

Spindlin-1, a multivalent epigenetic reader, is a new target for cancer therapy. Beside the anticancer effect, modulation of the recognition of methyl marks of histones may impact the immune system, which plays an important role in the anticancer strategy of the human organism. Two Spindlin-1 inhibitors (A366, MS31) were characterized to differentiate between drug and target-specific effects. We performed a comprehensive study regarding the influence of Spindlin-1 inhibition on various immune cells. A366 and MS31 showed immune cell type-dependent cytotoxicity with IC50 values in the ranges of 37-143 µM and 11-3122 µM, respectively, macrophages tending to be less susceptible than lymphocytes. A366 had only minor effects on M1 polarization, whereas MS31 shifted the M1 to a M2 phenotype, as shown by regulated cytokines and surface marker expression. Both A366 and MS31 weakened the polarization of predifferentiated M2 macrophages by reducing surface marker expression, cytokines, and inflammatory markers. A366 and MS31 had no effect on activation and energy metabolism of CD4+ T cells. Interestingly, 5 µM A366 and 2.5 µM MS31 clearly prevented B cell activation, as shown by reduced proliferation, plasmablast formation, and release of immunoglobulins A and G. Additionally, A366 increased energy metabolism in B cells. In conclusion, the inhibition of Spindlin-1 had only minor effects on polarization of macrophages and T cell proliferation but profoundly prevented B cell activation at low concentrations. This suggests that Spindlin-1 inhibitors, while mediating anticancerogenic effects, may also suppress the humoral immune response and increase infection risk.