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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2024-2030
Cyclophosphamide induces type I interferon and augments the
number of CD44hi T lymphocytes in mice:
implications for strategies of chemoimmunotherapy of cancer
Giovanna Schiavoni,
Fabrizio Mattei,
Tiziana Di Pucchio,
Stefano M. Santini,
Laura Bracci,
Filippo Belardelli, and
Enrico Proietti
From the Laboratory of Virology, Istituto Superiore di Sanità,
Rome, Italy.
In a previous study, we reported that a single injection of
cyclophosphamide (CTX) in tumor-bearing mice resulted in tumor eradication when the animals were subsequently injected with
tumor-sensitized lymphocytes. Notably, CTX acted by inducing bystander
effects on T cells, and the response to the combined CTX/adoptive
immunotherapy regimen was inhibited in mice treated with antibodies to
mouse interferon (IFN)- / . In the present study, we have
investigated whether CTX induced the expression of type I IFN, and we
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 with IFN detection in the majority of the animals. CTX
also enhanced the expression of the Ly-6C on spleen lymphocytes. This
enhancement was inhibited in mice treated with anti-type I IFN
antibodies. Moreover, CTX induced a long-lasting increase in in vivo
lymphocyte proliferation and in the percentage of
CD44hiCD4+ and CD44hiCD8+
T lymphocytes. These results demonstrate that
CTX is an inducer of type I IFN in vivo and enhances the number of T
cells exhibiting the CD44hi memory phenotype. Since type I
IFN has been recently recognized as the important cytokine for the in
vivo expansion and long-term survival of memory T cells, we suggest
that induction of this cytokine may explain at least part of the
immunomodulatory effects observed after CTX treatment. Finally, these
findings provide a new rationale for combined treatments with CTX and
adoptive immunotherapy in cancer patients.
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