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Induction of Highly Immunogenic Variants of Lewis Lung Carcinoma Tumor by Ultraviolet Irradiation

Biological Therapeutics Branch, Biological Response Modifiers Program, Division of Cancer Treatment, National Cancer Institute, NIH, Frederick Cancer Research Facility, Frederick, Maryland 21701

This study was undertaken to determine whether in vitro treatment of Lewis lung carcinoma (3LL) cells with ultraviolet (UV) radiation could increase their immunogenicity. Tumor cells were irradiated with UV light from a germicidal lamp (254 nm; UV-C) at a dose of 720 J/sq m. After 2 weeks of culture, the surviving cell population was cloned by limiting dilution. Cell suspensions of each clone were injected intrafootpad in C57BL/6 mice at a dose of 2.5 x 10⁵ cells per mouse. Eighty independent clones were tested. Fifty-one clones showed decreased tumorigenicity and failed to grow in 20 to 95% of immunocompetent mice, whereas they produced tumors in 100% of irradiated (550 R) and athymic nude mice. These clones were designated "tum^-" (nontumorigenic) clones. In contrast, all 25 clones selected from the untreated parental 3LL induced progressively growing tumors in 100% of the mice. After two courses of UV treatment, the uncloned 3LL population was rejected in 45% of inoculated mice. Mice rejecting an inoculum of a tum^- clone were completely resistant to subsequent challenge with higher doses of the same or unrelated tum^- clones. This resistance was fully expressed even after irradiation of immune mice with 550 R. Mice immune to a tum^- clone also were able to prevent the growth of various tum⁺ clones or untreated 3LL tumor cells. When tum^- and tum⁺ clone cells were simultaneously inoculated intrafootpad in opposite legs, rejection of tum^- clone resulted also in the prevention of the growth of tum⁺ clone. Spleen cells of immune mice caused rapid elimination of radiolabeled 3LL tumor cells from the place of their inoculation (intrafootpad) and prevented tumor growth. In an in vitro cytotoxic assay, spleen cells after in vivo and in vitro immunization with tum^- clones demonstrated high cytotoxic activity against various tum⁺ clones and parental 3LL cells, as well as against tum^- clones. In addition, parental 3LL tumor cells and tum^- cells were similarly able to inhibit cytotoxic activity in the cold target inhibition assay. However, in contrast to tum^- cells, 3LL cells were less efficient in in vitro restimulation of cytotoxic activity of immune spleen cells. Therefore, these data suggest that tum^-, tum⁺, and parental 3LL cells share a common antigenic specificity, which is not immunogenic in 3LL cells. UV treatment presumably converted the antigenic determinants present in the 3LL cells into an immunogenic form.

Received 6/ 4/84. Revised 11/ 5/84. Revised 2/ 7/85. Accepted 2/12/85.

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