(1) Background: Notwithstanding numerous therapeutic advances, 176,000 deaths from breast and
lung cancers will occur in the United States in 2021 alone. The tumor microenvironment and its modulation by drugs have gained increasing attention and relevance, especially with the introduction of
immunotherapy as a standard of care in clinical practice.
Retinoid X receptors (RXRs) are members of the
nuclear receptor superfamily and upon
ligand binding, function as
transcription factors to modulate multiple cell functions.
Bexarotene, the only FDA-approved RXR agonist, is still used to treat
cutaneous T-cell lymphoma. (2) Methods: To test the immunomodulatory and anti-
tumor effects of MSU42011, a new RXR agonist, we used two different immunocompetent murine models (MMTV-Neu mice, a HER2 positive model of
breast cancer and the A/J mouse model, in which
vinyl carbamate is used to initiate lung
tumorigenesis) and an immunodeficient xenograft
lung cancer model. (3) Results: Treatment of established
tumors in immunocompetent models of HER2-positive
breast cancer and Kras-driven
lung cancer with MSU42011 significantly decreased the
tumor burden and increased the ratio of CD8/CD4, CD25 T cells, which correlates with enhanced anti-
tumor efficacy. Moreover, the combination of MSU42011 and
immunotherapy (anti-PDL1 and anti-PD1
antibodies) significantly (p < 0.05) reduced
tumor size vs. individual treatments. However, MSU42011 was ineffective in an athymic human A549
lung cancer xenograft model, supporting an immunomodulatory mechanism of action. (4) Conclusions: Collectively, these data suggest that the RXR agonist MSU42011 can be used to modulate the tumor microenvironment in breast and
lung cancer.