Tumor-associated macrophages (TAMs) compose immunosuppressive cancer stroma by various pathways. Since TAMs produce specific chemokines by the stimulation of various factors including drug administration, TAMs could be a target for cancer therapy. As we previously reported, cancer stroma on mycosis fungoides (MF) contains dense deposition of periostin (POSTN) in early stage, whereas the expression of IL-4 is prominent instead of POSTN deposition in advanced stage, leading the different biological behavior of each stage of MF. Bexarotene is a third-generation retinoid X receptor (RXR)-selective retinoid, and administered for the treatment for MF though the mechanisms of its anti-tumor effects are diverse. The purpose of this study was to evaluate the potencies of bexarotene, focusing on its effects on TAMs. As we previously reported, DNA microarray database of macrophages stimulated by POSTN or IL-4 suggested CXCL5 could be a useful marker for early MF, while CCL22 could be for advanced MF. Double immunofluorescence staining of cryosections with combinations of antibodies against CCL22/ CXCL5 and CD163 revealed that CD163 macrophages mainly produce CCL22 and CXCL5. To explore the effects of bexarotene on CD163+ macrophages, we generated CD163+ macrophages from CD14+ PBMC, and co-cultured with or without bexarotene, leading the decrease of mRNA expression and production of CCL22 and CXCL5. Furthermore, the serum CCL22 was decreased by oral administration of bexarotene in patinents with early and advanced MF, while serum CXCL5 is augmented in advanced MF. Our present data suggested that bexarotene modulates chemokine production from TAMs, leading its therapeutic effects in both early and advanced MF.

Immunomodulatory effects of bexarotene on tumor-associated macrophages in patients with mycosis fungoides.