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Mutagen Treatment As a Means for Selecting Immunogenic Variants from Otherwise Poorly Immunogenic Malignant Murine Tumors1

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Mutagen Treatment As a Means for Selecting Immunogenic Variants from Otherwise Poorly Immunogenic Malignant Murine Tumors1 [CANCER RESEARCH 43, 125-132, January 1983] 0008-5472/83/0043-OOOOS02.00 Mutagen Treatment as a Means for Selecting Immunogenic Variants from Otherwise Poorly Immunogenic Malignant Murine Tumors1 Philip Frost,2 Robert S. Kerbel,3 Elaine Bauer,2 Rose Tartamella-Biondo,4 and William Cefalu Department of Medicine, Long Beach Veterans Administration Hospital, Long Beach. California 90822 [P. F., E. B.. W. C.J: Departments of Medicine and Microbiology, University of California. Irvine. California ¡P.F.. R. T-B.j; and the Cancer Research Laboratories. Department of Pathology, Queens University, Kingston, Ontario, Canada [R. S. K.] ABSTRACT found to be nontumorigenic (turn ) and grew progressively only in highly immunosuppressed recipients such as 600-R X-irra- The selection of nontumorigenic (turn'), highly immunogenic diated hosts (4-6, 27-29). Three different tumors were used, variants from four different tumorigenic but poorly immuno namely, the PCC4 teratocarcinoma (4, 5), the P815 mastocy- genic murine tumors by mutagen treatment and cloning is toma (6, 27), and the Lewis lung carcinoma (29). In all cases, described. Several factors were found to determine the suc cloning of these tumors after treatment with MNNG resulted in cessful nature of this selection procedure including: the nature the selection of highly immunogenic tum~ variants at an ex of the tumor used; the nature of the mutagen; the number of traordinarily high frequency. These variants were shown to mutagen treatments; and the time at which cloning is performed share antigens with the parent tumor as well as each other; in after treatment. addition, they expressed a newly induced unique or private In some cases, e.g., the TA3 adenocarcinoma or the BALB/ antigen. We have recently discussed the considerable impor e SS1 spontaneous mammary adenoacanthoma, a single treat tance and implications of these results in relation to recognition ment with ethyl methanesulfonate or A/-methyl-A/'-nitro-/v-nitro- of tumor antigens by the immune system as well as for immu- soguanidine led to a very high frequency of turn" clones, notherapy of poorly immunogenic tumors, such as those of whereas in others, e.g., the MDAY-D2 tumor line, no stable turn" clones were obtained. The immunogenic clones selected spontaneous origin (20). We herein describe our own experience with additional mu were always immunologically cross-reactive with the parent rine tumors (including one nonimmunogenic spontaneous tumor from which they were derived and were found to protect BALB/c carcinoma) and a different mutagen, namely, EMS. the murine host against challenge with the parent tumor in vivo. Our findings confirm some of those of Boon and his colleagues Thus, the cloned immunogenic variants share an antigen with but also point toward additional complexities in this model the parent tumor. Additional evidence, however, suggested relating to the nature of the mutagen used, the tumor cell type that each clone also expresses a new private or unique antigen. used, and the timing of cloning after mutagen treatment. The frequency of immunogenic variant selection ranged from a low of 6% to a high of 95%. In some cases in which the MATERIALS AND METHODS frequencies were very high, cloning was not required to reveal the turn" phenotype. Finally, we also noted that selection for Animals. DBA/2 and A strain mice, 5 to 6 weeks old, were pur drug resistance, e.g., resistance to 6-thioguanine, after muta- chased from The Jackson Laboratory, Bar Harbor, Maine. BALB/c mice were originally obtained from the NIH, Bethesda, Md., and are genesis could have an enhancing effect on the generation of highly immunogenic turn" clones. The results show that the currently bred in our colony at the Long Beach Veterans Administration Hospital. BALB/c-nu/nu mouse breeding pairs were originally ob immunogenicity of poorly immunogenic tumors, including those tained from the NIH and are currently maintained in our own nude of spontaneous origin, can be dramatically enhanced by ap mouse colony established at the Long Beach Veterans Administration propriate mutagen treatments but that there is considerable Hospital. In all experiments aimed at assessing the growth potential of variation in the ease with which highly immunogenic variants tutrr variants, both nu/nu and nu/+ heterozygous littermates were can be obtained. challenged with tumor. Tumors. The origin and characteristics of the MDAY-D2 tumor have been described in detail elsewhere (11, 19, 21). The P815 mastocy- INTRODUCTION toma was obtained from Dr. R. Herberman (NIH). The TA3 mammary adenocarcinoma was obtained through Dr. Joseph G. Mayo, NIH, and In a series of papers, Boon et al. (4-6, 27-29) reported that Dr. Arthur Bogden, Mason Research Institute Tumor Bank, Worcester, treatment of murine tumor cells with the mutagen MNNG5 Mass. The SS1 adenoacanthoma is a spontaneous mammary tumor results in the generation of highly immunogenic variants. The derived from a BALB/c female in the colony maintained at the Clinical increased immunogenicity was so marked that the clones were Research Center, Harrow, England. SS1 grows in BALB/c mice de rived from the NIH colony. It does not grow in histoincompatible strains. 1Supported by the Medical Research Council of Canada. Although this tumor was isolated 8 years ago, it was stored in liquid 3 Recipient of a grant from the Veterans Administration and Research Grant nitrogen after its third in vivo passage. This stock serves as the current CA 28060 from the USPHS. To whom requests for reprints should be addressed source of the SS1 tumor used in these experiments. Tumor cells were at Long Beach Veterans Administration Hospital, 9501 East 7th Street N-S, Long Beach, CA 90082. maintained in culture or by weekly i.p. passage. All cell lines were 3 Research Associate of the National Cancer Institute of Canada. routinely tested to assure that they are free of Mycoplasma by assess ' Recipient of a grant from the National Cancer Institute of Canada. ing for growth in pleuropneumonia-like organism agar plates and 5 The abbreviations used are: MNNG, W-methyl-W-nitro-N-nitrosoguanidine; modified Hayflick's broth medium under aerobic and anaerobic condi turn', nontumorigenic in normal immunologically intact syngeneic hosts; EMS, ethyl methanesulfonate; RPMI, Roswell Park Memorial Institute; CMC, cell-me tions. diated cytotoxicity; turn*, tumorigenic; met , nonmetastatic; met*, metastatic. Treatment of Cells with Mutagens and Selection for Drug Resist Received May 6, 1982; accepted October 12, 1982. ance. Treatment of tumor cells with MNNG was performed according JANUARY 1983 125 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1983 American Association for Cancer Research. P. Frasi eíal. Protocol I ParentTumor -TreatedwithEMSorMNNG- Selectedfor UnclonedPopulation OuabainResistance InjectedS.C. TreatedwithEMS NoGrowth InVivo InVivo Chart 1. Schematic outline of treatment Select'!edfor6-Thioguanine with EMS of cells selected for resistance to Resistance, ouabain and 6-thioguanine. Only clones which SurvivorsareCloned Reinjectedx3* failed to grow after 3 sequential injections into different animals were considered to be turn". andRandomClonesare UnetonedPopulation Cloned Injected NoGrowth Grows Injected InVivo InVivo Individual NoGrowth Grows Clones In Vivo h Vivo Injected Grows NoGrowth 3;rowth x I X InVivo InVivo Reinjectediti Grows | Not Grows 1 mVivo Reflected In\flvo InVivo NoGrowth NoGrowth\ x3Grows mvivo InVivo NoGrowth InVivo InVivoReinjected -AssessedforAbilitytoGenerateCMCResponseandforCross ReactivitywithParentTumorInVivoandInVitro to the methods of Boon and Kellerman (4). Cells (3 x 106in 5 ml) were Fc Receptor Assay. Fc receptors were assessed using the method exposed to MNNG at 3 fig/ml for 60 min. The cells were washed and described by Kerbel (18). The antiserum used was a monoclonal lgG2B placed in culture. Treatment with EMS was according to the method of anti-sheep RBC antibody derived from a hybrid myeloma designated Gillin et al. (13) as modified by Wasmuth.6Five ml of tumor cells at 6 Sp 2/HL by Kohler and Milstein (22). This antiserum was purchased x 105cells/ml were placed in small sterile Retri dishes and allowed to from Sera Labs (Crawley Downs, Sussex, England). equilibrate to a 5% CO2atmosphere in RPMI without fetal calf serum. Radiolabeling of Tumor Cells. The radiolabeling of tumor cells with After 1 hr, 2.5 /il (0.5 fil/ml) of EMS were added, and the cells were ['"ln]indium oxine is based on methods that we have described previ allowed to incubate for 2 hr, after which they were centrifuged and ously (12). Briefly, cells were labeled with 30 fiCi [11'ln]indium oxine at incubated in RPMI with 10% fetal calf serum. Under these conditions, a concentration of 107 cells/0.5 ml in RPMI Medium 1640 with 10% cell viability is reduced to approximately 30% after 24 hr. This is fetal calf serum and 20 mw N-2-hydroxyethylpiperizine-W-2-ethane- consistent with the findings of others (4).6 For drug selection, the cells sulfonic acid buffer for 15 min at 37°and washed 3 times in 15 ml of were exposed to either 6-thioguanine (8.5 fig/ml) or 1 rriMouabain 4 medium. to 5 days after EMS treatment. The drug dose was increased each time CMC Assay. CMC was assessed by a method described previously confluent cell growth occurred until resistance to 6-thioguanine (15 (19, 30). In initial experiments, individual spleens from 5 mice were jug/ml) or 3 rriMouabain was achieved. Cells selected for resistance to tested for their CMC activity. The results demonstrated almost identical both drugs were treated for a second time with EMS and carried reactivity. Subsequent experiments have therefore used pools of 3 to through the same procedure. A schematic outline of these procedures 5 immune spleens. is shown in Chart 1. The CMC assay was performed in round-bottomed microplates (Fal Assessment of Métastases.TheMDAY-D2 tumor metastasizes in con) by mixing effector and target cells at desired ratios in triplicate in a widespread and aggressive manner (11, 21).
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