Impact of hyaluronic acid on cutaneous T-cell lymphoma microenvironment: A novel anti-tumor mechanism of bexarotene

Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin lymphoma that primarily affects the skin rich in hyaluronic acid（HA）. HA composes extracellular matrix in the dermis, which likely affects the development of CTCL but is poorly understood. Here, we show that low molecular weight HA (LMWHA) possibly exacerbates CTCL in mouse and human specimens, and bexarotene already being used in CTCL treatment can decrease HA production. Patients’ serum and skin sections showed higher HA expression than healthy controls. HA extracted from the skin of mice inoculated with tumors showed an increase in LMWHA. LMWHA increased lymphoma cell proliferation in vitro and accelerated tumor formation in mice in vivo. LMWHA also created a favorable environment for tumor cells by influencing fibroblasts, vascular endothelial cells, and tumor-associated macrophages. Together, increased HA, mainly LMW aids in CLCL progression by affecting tumor cells and microenvironment. Next, bexarotene treatment reduced the amount of total HA in murine tumor-inoculated skin and the supernatant of cultured normal human dermal fibroblasts (NHDFs) and HuT78 cells. Detailed in vitro assessments showed that bexarotene treatment decreased hyaluronic acid synthase (HAS) 1 and HAS2 expression in NHDFs and HAS1, HAS3, and CEMIP in HuT78. Chromatin immunoprecipitation assay revealed bexarotene reduced retinoid X receptor-alpha binding to the HAS1 and HAS2 promoters in NHDFs. Bexarotene potentially exerts its anti-tumor effect by reducing HA through decreased expression of HA synthase. These findings provide us with new insights into the developmental process of CLCT and additional insight into bexarotene treatment.