High-dose cyclophosphamide-mediated anti-tumor effects by the superior expansion of CD44^high cells after their selective depletion

As alkylating agents, cyclophosphamides (CTX) are used to treat various cancers and, ironically, to boost immune responses. In the present study, we attempted to elucidate the mechanism responsible for the immunomodulatory effect of high-dose CTX in an established tumor model. A single injection of high-dose CTX increased the survival rate of immunocompetent, but not immunodeficient, mice. Notably, 10 days after CTX injection, the number of CD44^high memory T cells significantly increased, without a selective decrease in the actual number and percentage of CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs). However, the proportion of Tregs among CD4⁺ T cells decreased due to expansion of memory and other CD4⁺ T cell subtypes. This outcome was accompanied by an increase in IL-15 mRNA and up-regulation of IL-15 receptors in the CD44⁺CD8⁺ T cell compartment. We postulate that the CTX-induced change in T cell balance may increase anti-tumor immunity.