A novel RXR agonist suppresses tumor formation accompanied by increased CD8+ T cells in a murine model of cutaneous T cell lymphoma (CTCL)

Summary: Abstract Body: Nuclear retinoid X receptors (RXRs) play critical roles in developmental, metabolic, biochemical, and immunomodulatory processes via dimerization and ligand activation. Bexarotene (Bex), the first and only FDA-approved RXR-targeted agonist for cutaneous T-cell lymphoma (CTCL), promotes tumor cell differentiation and apoptosis. With limited patient response to bexarotene and adverse effects such as hepatotoxicity and hypertriglyceridemia, more effective and safer RXR agonists for cancer therapy are needed. Using our published method, murine MBL2 T cell lymphoma cells were subcutaneously injected in the ear skin of mice, followed by a single topical application of dinitrofluorobenzene (DNFB), inducing tumor formation as early as day 7 in an inflammatory tumor microenvironment (TME). To test RXR drugs, mice were fed a powdered chow mixed with either Bex or a novel RXR agonist, ASU052317 (ASU), starting on day 3 after tumor inoculation. After one week of treatment, ASU significantly inhibited tumor growth compared to the control diet, while Bex showed no inhibitory effect (Turkey’s multiple comparisons: p=0.0043 for Bex vs. ASU; n=6). Flow cytometry and microscopy analyses revealed that ASU, but not Bex, markedly altered immune profiles relative to normal and vehicle-treated groups, particularly by increasing CD8+ lymphocyte numbers in both the spleen (p<0.01) and the TME, where these cells densely accumulated at the invasive edges of tumors (p<0.01). Importantly, these CD8+ lymphocytes lacked PD-1 expression, suggesting they retained cytotoxic functionality. As expected, Bex treatment elevated serum triglycerides and cholesterol levels, while ASU-treated mice showed no such abnormalities. Thus, ASU052317 reduced tumor formation (accompanied by an anti-tumor response) in a murine CTCL model without affecting the lipid profile in treated mice, prompting further exploration of unique RXR agonists for CTCL. Xuesong Wu¹, Ana S. Leal^{2, 4}, Peter Jurutka³, Karen Liby^{2, 4}, John Freshley², Samuel Hwang¹ 1. University of California Davis, Sacramento, CA, United States. 2. Akeila Bio, Ann Arbor, MI, United States. 3. Arizona State University, Tempe, AZ, United States. 4. Indiana University, Bloomington, IN, United States. Translational Studies: Preclinical