Modulation of Antitumor Immunity of Tumor-Bearing Mice with Low-Dose Cyclophosphamide

Abstract

As a tumor progressively grows, the tumor-bearing host usually is under a tumor-mediated immune suppression status. Although surgical resection of the tumor may immediately eliminate most tumor-induced detrimental influences, perioperatively the antitumor immunity of the host remains temporarily suppressed. The major purpose of this study is to investigate the modulation effect of low-dose cyclophosphamide (CY) on the 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 significantly enhance the specific antitumor immunity of the TBM. It consequently suppresses the outgrowth of perioperative rechallenged tumor cells 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 reduction of both absolute number and percentage of cells with CD4−CD8−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 CD4+/CD8+ratio remains unchanged. However, after short-termin vitroculture with IL-2 the percentage of the CD4−CD8−subset and CD4+/CD8+ratio markedly decreased because of the relatively predominant proliferation of the CD4−CD8+subset. Evidence fromin vitrocytotoxicity assays on panel tumor cells and phenotypic analysis revealed that this enhancement of host antitumor immunity, following low-dose CY pretreatment, may be due to augmenting the activity of NK, LAK, and CD11b+myeloid/macrophages in addition to cytotoxic T lymphocytes.