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Mechanisms of in Vivo Generation of Cytotoxic Effector Cells against Tumor in Tumor-bearing Mice

Department of Pathology, Yamagata University School of Medicine, Iida, Zao, Yamagata 990-23, Japan

Our previous study showed that spleen cells from BALB/c mice bearing RL1 lymphoma inhibited the growth of RL1 lymphoma by the Winn-type adoptive transfer assay. Although this antitumor activity was mediated by the T-cell subset manifesting the surface phenotype of cytotoxic T-lymphocytes (CTLs), this antitumor activity of spleen cells was not detected by the in vitro cell-mediated cytotoxicity assay (4-h ⁵¹Cr release assay). The present study is concerned with the hypothesis that the maturation of the CTLs directed against RL1 may be arrested in spleens of the RL1-bearing mice and the differentiation into mature CTLs may occur at the tumor site; i.e., the immature CTLs (activated precytotoxic T-cells) may acquire the killing activity when they contact tumor cells at the tumor site.

This report shows that BALB/c mice bearing the progressive RL1 lymphoma were able to generate CTLs against RL1 in the peritoneal cavities when the mice were inoculated i.p. with the irradiated RL1 cells. The cytotoxic activity of the peritoneal exudate cells of the RL1-bearing mice appeared 3 to 5 days after i.p. inoculation of the irradiated RL1 cells and rapidly decreased on day 7 after inoculation. In addition, spleen cells from the RL1-bearing mice after i.p. inoculation of the irradiated RL1 cells were not cytotoxic, suggesting a highly localized response. The cytotoxic effector cells induced in the peritoneal cavities consisted of T-lymphocytes and natural killer cells. Both cell types were simultaneously induced in the peritoneal cavities of the RL1-bearing mice. The T-cell subset mediating cytolytic activity against RL1 was shown to consist of Lyt-1⁺2⁺ T-cells which were defined by cytolysis with anti-Lyt-1 or anti-Lyt-2 antibody and complement. On the other hand, the normal BALB/c mice inoculated i.p. with the irradiated RL1 cells generated natural killer cells in the peritoneal cavities and spleens but the CTLs were not induced. The results from the present and previous studies suggest that precytotoxic or immature cytotoxic T-cells in spleens of the tumor-bearing mice migrate into the circulation and then mature CTLs develop at the tumor site.

¹ To whom requests for reprints should be addressed.

Received 5/ 8/86. Revised 7/14/86. Accepted 7/17/86.