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Imaging of Activated Natural Killer Cells in Mice by Positron Emission Tomography: Preferential Uptake in Tumors¹

Departments of Radiation Oncology [R. J. M., R. K. J.] and Radiology [A. L. B., T. M. S., G. L. B.], Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114

Optimal delivery of immunologically active cells to target tissue(s) is important for improving adoptive immunotherapy of neoplastic diseases. By using positron emission tomography, we have measured the systemic distribution and tumor localization of locally injected, activated natural killer (NK) cells or nonactivated lymphocytes in the FSaII fibrosarcoma grown s.c. in the tail of C3H mice. Murine NK cells were isolated and expanded in the presence of interleukin 2 and collected at 5 to 7 days after culture. These cells were then washed and labeled with [¹¹C]methyl iodide, a positron-emitting isotope. Ten million activated or nonactivated cells were injected into the lateral tail vein distal to the tumor over a period of 2 min, and the accumulation of counts in the tumor was monitored during the injection and at 30–60 min postinjection. There was no significant difference in the rate of accumulation of activated NK cells (685 ± 264 (SE); n = 5) versus nonactivated splenic lymphocytes (595 ± 105; n = 5) during the injection period. Whole body scans of the mice done at 30 min to 1 h postinjection showed that the number of activated cells retained within the tumor ranged from 4 to 30% (15.3 ± 4.9%; n = 5) of the injected dose. Activated NK cells which were not retained by the tumor accumulated in the lungs, liver, and spleen. In contrast, from 3 to 4% (3.4 ± 0.2%; n = 5) of nonactivated lymphocytes remained within the tumor by 1 h. Nonactivated cells were distributed more homogeneously throughout the systemic circulation than the activated cells, although these cells also demonstrated increased retention in the lungs, liver, and spleen. The present study demonstrates that positron emission tomography may be used to quantify the number of effector cells which accumulate within tumors and to determine their biodistribution. The retention of labeled cells within the tumor may also be used as a means of imaging the tumor. Finally, the preferential accumulation of effector cells in the tumor vasculature following local injection has useful implications for adoptive immunotherapy.

¹ Work supported by the American Cancer Society (IM-527) and the Department of Energy (DE-FG02-87ER60519). Preliminary reports presented at the 1993 annual meetings of the American Association for Immunology (Denver, CO) and Nuclear Medicine Society (Toronto, Canada).

Received 8/24/93. Accepted 11/ 2/93.

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