Antitumor effector mechanism of interleukin-1 beta at a distant site in the double grafted tumor system.

Recombinant human interleukin-1 beta (IL-1 beta) inhibited the growth of not only the right, but also the left non-treated tumor in a double grafted tumor system. Since the antitumor activity of IL-1 beta against the right and left tumors was not seen in nude mice, lymphocytes have a key role in the antitumor effect of intratumoral administration of IL-1 beta. TIL (tumor-infiltrating leukocytes) obtained from left and right side tumors treated with IL-1 beta were examined by Winn assay for their antitumor activity against Meth-A sarcoma in BALB/c mice. TIL from the right side clearly inhibited the growth of admixed Meth-A cells, but control TIL did not. Spleen cells and right and left regional lymph node cells prepared from IL-1-treated mice were examined for Lyt-1, Lyt-2 and L3T4 phenotypes. The number of Lyt-1-positive lymphocytes increased in the spleen and in the right regional lymph nodes after intratumoral administration of IL-1. Isolated tumor cells obtained from the right tumor treated with IL-1 beta and the left side tumor on day 6 were cultured in RPMI 1640 with 10% fetal calf serum for 24 h. The culture supernatants were harvested and tested for the presence of chemotactic activity for neutrophils or macrophages. Significant neutrophil chemotactic factor and macrophage chemotactic factor activities were detected in the culture media from IL-1-treated tumor tissues cultured for 24 h. Neither significant neutrophil nor macrophage chemotactic activity was detected in the media from untreated tumor tissues. These results suggest that intratumoral administration of IL-1 first induces neutrophils and macrophages in the right tumor, then Lyt-1-positive cells in the right regional lymph nodes and in the spleen, and subsequently induces macrophages in the left, non-treated tumor.