MODULATION OF ANTITUMOR IMMUNITY OF TUMOR-BEARING MICE WITH LOW-DOSE CYCLOPHOSPHAMIDE

As a tumor progressively grows, the tumor-bearing host usually is unde r a tumor-mediated immune suppression status. Although surgical resect ion of the tumor may immediately eliminate most tumor-induced detrimen tal influences, perioperatively the antitumor immunity of the host rem ains temporarily suppressed. The major purpose of this study is to inv estigate the modulation effect of low-dose cyclophosphamide (CY) on th e antitumor immunity of tumor-bearing mice (TBM). Using the C3H/He-MBT -2 murine bladder tumor model, we demonstrate that low-dose CY (100 mg / kg) intraperitoneal injection 2 days before tumor resection can sign ificantly enhance the specific antitumor immunity of the TBM. It conse quently suppresses the outgrowth of perioperative rechallenged tumor c ells and improves the survival of the animals. Phenotypic analysis of cellular subset of spleen by flow cytometry revealed that low-dose CY, when given to both naive and tumor-bearing mice, causes significant r eduction of both absolute number and percentage of cells with CD4(-)CD 8(-) subset in the spleens of TBM. As a result of a parallel increase in the percentage of both CD4(+)CD8(-) and CD4(-)CD8(+) subsets, the C D4(+)/CD8(+) ratio remains unchanged. However, after short-term in vit ro culture with IL-2 the percentage of the CD4(-)CD8(-) subset and CD4 (+)/CD8(+) ratio markedly decreased because of the relatively predomin ant proliferation of the CD4(-)CD8(+) subset. Evidence from in vitro c ytotoxicity assays on panel tumor cells and phenotypic analysis reveal ed that this enhancement of host antitumor immunity, following low-dos e CY pretreatment, may be due to augmenting the activity of NK, LAK, a nd CD11b(+) myeloid/macrophages in addition to cytotoxic T lymphocytes . (C) 1996 Academic Press, Inc.