Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner

Background: Chemotherapy is included in treatment regimens for many solid cancers, but when administered as a single agent it is rarely curative. The addition of immune checkpoint therapy to standard chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy. Methods: We used gene expression data from cyclophosphamide (CY) responders and non-responders to identify existing clinically approved drugs that could phenocopy a chemosensitive tumor microenvironment (TME), and tested combination treatments in multiple murine cancer models. Results: The vitamin A derivative tretinoin was the top predicted upstream regulator of response to CY. Tretinoin pre-treatment induced an inflammatory, interferon-associated TME, with increased infiltration of CD8 + T cells, sensitizing the tumor to subsequent chemotherapy. However, while combination treatment significantly improved survival and cure rate in a CD4⁺ and CD8⁺ T cell dependent manner in AB1-HA murine mesothelioma, this effect was model-selective, and could not be replicated using other cell lines. Conclusions: Despite the promising data in one model, the inability to validate the efficacy of combination treatment in multiple cancer models deprioritizes tretinoin/cyclophosphamide combination therapy for clinical translation.