A model for vorinostat activity in HL. HL is characterized by the presence of abundant numbers of dendritic cells (DCs) and Th2-type CD4 cells in the microenvironment. HRS cells aberrantly express activated STAT6 by an autocrine IL-13 loop. Both DC and HRS cells secrete TARC that attracts TH2 type cells. In this model, vorinostat has a dual effect on HL. (A) A direct effect on HRS cells by modulating a variety of growth and survival proteins, including p21 and Akt, in addition to inhibiting STAT6 transcription. Inhibition of STAT6 decreases Bcl-xL protein levels causing apoptosis, and decreases TARC secretion causing inhibition of Th2-type CD4⁺ cell chemotaxis. (B) An indirect effect on DCs in the microenvironment. Thymic stromal lymphopoietin (TSLP) activates myeloid DCs (mDCs) to express OX40 ligand (OX40L) and to secrete TARC, favoring polarization and attraction of TH2-type CD4⁺ cells. Vorinostat inhibits TRAC secretion by DCs, thus modulating the function and component of the reactive cells in HL microenvironment.