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Enhanced Induction of Very Late Antigen 4/Lymphocyte Function-associated Antigen 1-dependent T-Cell Migration to Tumor Sites following Administration of Interleukin 12¹

Biomedical Research Center [M. O., T. T., J-P. Z. J. M., R. W., W-G. Y., H. F., T. H.] and Department of Otorhinolaryngology [T. K.], Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565, Japan and Genetics Institute, Inc., Cambridge, Massachusetts 02140 [S. H.]

Administration of interleukin 12 (IL-12) into mice bearing CSA1M, OV-HM, Meth A, or MCH-1-A1 tumor induced complete regression of CSA1M and OV-HM tumors but induced only a slight growth inhibition of Meth A and MCH-1-A1 tumors. These effects of IL-12 were associated with high and only marginal levels of T-cell infiltration into CSA1M/OV-HM and Meth A/MCH-1-A1 tumor masses, respectively. Here, we investigated the role of IL-12 in the induction of T-cell migration. Spleen cells from untreated or IL-12-treated CSA1M-bearing mice were stained in vitro with a fluorescein chemical and transferred i.v. into IL-12-untreated CSA1M-bearing mice. Migration of donor cells was quantitated by counting the number of fluorescent cells on cryostat sections of tumor masses. Although only a slight migration was detected for spleen cells from IL-12-untreated CSA1M-bearing as well as IL-12-treated or untreated normal mice, enhanced migration was observed for cells from IL-12-treated CSA1M-bearing mice. A similar enhanced migration was observed for the OV-HM model. In contrast, such an enhancement was only marginal in the Meth A and MCH-1-A1 models. Immunohistochemical studies of tumors from IL-12-treated mice revealed that the predominant T-cell subset was CD4⁺ in CSA1M and CD8⁺ in OV-HM tumor masses. Consistent with this observation, the dominant subset of migrating T cells was found to be CD4⁺ in the CSA1M and CD8⁺ in the OV-HM models. T-cell migration was inhibited by pretreatment of recipients with either combination of anti-very late antigen 4 + anti-vascular cell adhesion molecule 1 or anti-lymphocyte function-associated antigen 1 + antiintercellular adhesion molecule 1 monoclonal antibody. These results indicate that IL-12 can confer T cells with a capacity to migrate to tumor sites through very late antigen 4/lymphocyte function-associated antigen 1 adhesion pathways and that the in vivo acquisition of such a capacity following IL-12 treatment correlates with the induction of tumor regression.

¹ This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan.

² To whom requests for reprints should be addressed. Phone: 81-06-879-3982; Fax: 81-06-879-3989.

Received 12/10/96. Accepted 4/ 3/97.

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