Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer

In a previous study, we reported that a single injection of cyclophosphamid e (CTX) in tumor-bearing mice resulted in tumor eradication when the animal s were subsequently injected with tumor-sensitized lymphocytes, Notably, CT X acted by inducing bystander effects on T cells, and the response to the c ombined CTX/adoptive immunotherapy regimen was inhibited in mice treated wi th antibodies to mouse interferon (IFN)-alpha/beta. In the present study, w e have investigated whether CTX induced the expression of type I IFN, and w e have characterized the CTX effects on the phenotype of T cells In normal mice. CTX injection resulted in an accumulation of type I IFN messenger RNA in the spleen of inoculated mice, at 24 to 48 hours, that was associated w ith IFN detection in the majority of the animals. CTX also enhanced the exp ression of the Ly-6C on spleen lymphocytes. This enhancement was inhibited In mice treated with anti-type I IFN antibodies. Moreover, CTX induced a lo ng-lasting increase in in vivo lymphocyte proliferation and in the percenta ge of CD44(hi)CD4(+) and CD44(hi)CD8(+) T lymphocytes, These results demons trate that CTX is an inducer of type I IFN in vivo and enhances the number of T cells exhibiting the CD44(hi) memory phenotype. Since type 1 IFN has b een recently recognized as the Important cytokine for the in vivo expansion and long-term survival of memory T cells, we suggest that induction of thi s cytokine may explain at least part of the immunomodulatory effects observ ed after CTX treatment. Finally, these findings provide a new rationale for combined treatments with CTX and adoptive immunotherapy In cancer patients , (C) 2000 by The American Society of Hematology.