CYCLOPHOSPHAMIDE TREATMENT OF AN SJL MURINE B-CELL LYMPHOMA INCREASES THE PROPORTION OF SUPPRESSIVE CD8+ OVER TUMOR-STIMULATORY CD4+ T-LYMPHOCYTES

Lymphomas (formerly reticulum cell sarcomas (RCS)) which develop spontaneously in SJL mice are a murine counterpart of human low grade B-cell non-Hodgkin's lymphoma. Tumor cells stimulate proliferation of syngeneic CD4+ T-lymphocytes which secrete cytokines required for tumor growth. Cyclophosphamide treatment of tumor-bearing mice (RCS/Cy) decreases in vitro tumor-stimulated CD4+ T-cell proliferation and, in turn, tumor growth, in part, through the suppressive action of CD8+ T-lymphocytes. In RCS/Cy compared to untreated tumor-bearing (RCS5) mice we report marked in vivo decreases in: (1) the activation (CD44HI/CD45RB(LO) phenotype) and proliferation (S + G2M phases of the cell cycle) of CD4+ T-lymphocytes; (2) the ratio of activated and/or proliferating CD4+ to CD8+ T-lymphocytes, and; (3) the proliferation of tumor cells. Also, depletion of CD8+ T-lymphocytes from RCS/Cv mice abrogated much of the efficacy of the RCS/Cy treatment and led to changes in lymphoid populations more reminiscent of those in RCS5 than RCS/Cy mice. The data support our hypothesis that the RCS/Cy treatment achieves its efficacy by preventing the predominance of CD4+ over CD8+ T-lymphocytes which is essential to maximum tumor growth in RCS5 mice. The results imply that analogous B-cell lymphomas in humans also may be treatable by shifting the T-cell balance toward inhibitory CD8+ rather than the tumor-stimulatory CD4+ T-lymphocytes.