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Infiltrative and Cytolytic Activities of Lymphokine-activated Killer Cells against a Human Glioma Spheroid Model¹

Department of Neurosurgery, Kyoto University Medical School, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606, Japan

In the present study, we investigated not only the cytotoxic effects of lymphokine-activated killer (LAK) cells on a tumor mass but also the ultrastructural cell-to-cell interaction between LAK effector cells and tumor cells during the cytolytic process within a three-dimensional solid tumor. A multicellular tumor spheroid of a human glioma cell line (U-251MG) was utilized as a solid tumor model. LAK cells were generated from peripheral blood lymphocytes of a healthy donor after stimulation by interleukin 2. Multicellular tumor spheroids with diameters of 500 µm were cocultivated with either LAK cells or nonactivated peripheral blood lymphocytes at the effector:target cell ratio of 20:1, and then time-sequential kinetic, morphological, and ultrastructural analyses were carried out. Morphological and kinetic studies showed that LAK cells directly infiltrated toward the inner areas of multicellular tumor spheroids and caused a progressive tumor destruction. In contrast, peripheral blood lymphocytes hardly exhibited such activities. Ultrastructurally, it was found that the infiltrating LAK effector cells were composed of heterogeneous subpopulations, T-like cells, and large granular lymphocyte-like cells. Both types of lymphocytes tightly adhered to the tumor cells and showed typical morphological features of killing them.

¹ This work was supported in part by Grant-in-Aid for Cancer Research 63-17 for the Ministry of Health and Welfare of Japan.

² To whom requests for reprints should be addressed.

Received 6/13/89. Revised 12/19/89.