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Suppression of the Cytotoxic Response of Mouse Lymphocytes to Syngeneic Tumor Cells by Tumor-promoting Phorbol Ester¹

Departments of Microbiology and Pathology, Boston University School of Medicine, Boston, Massachusetts 02118

We have investigated the effects of tumor-promoting phorbol esters on the generation of T-killer cells against syngeneic tumor cells in tissue culture. C57BL/6 or BALB/c spleen cells were cultured with irradiated EL-4 or MPC-11 tumor cells, respectively, for 3 to 7 days at responder:stimulator ratios of 25:1 to 200:1. Lysis was measured in a 4-hr ⁵¹Cr release assay. During the sensitization phase, 12-O-tetradecanoylphorbol-13-acetate (TPA) at concentrations as low as 10 ng/ml inhibited the response by 90 to 100% at all responder:stimulator ratios and when added on Day 0, 1, 2, or 4 of a 5-day assay. Thus, TPA was able to suppress the response following successful activation of lymphocytes, since cytotoxicity could be detected as early as Day 3. Addition of TPA on Day 0 caused complete suppression of lysis when measured on Day 3, 5, or 7, indicating that the suppression was not due to a change in the kinetics of the cytotoxic response. The degree of suppression caused by five different phorbol compounds was positively correlated with their tumor-promoting activity. TPA was much less suppressive when added at the effector phase. Indomethacin, an inhibitor of prostaglandin synthesis, did not reverse the TPA effect even when added daily, beginning 3 days before the addition of TPA. The data suggest that one mechanism of phorbol ester tumor promotion may be the inhibition of T-cell immunity against tumor cells initiated by carcinogens.

¹ Research supported by Grants CA31792, HL28451, AI18811, and CA21401 from the NIH and IM-129 from the American Cancer Society.

² Present address: Department of Pathology, University of Texas Health Science Center at Dallas, Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, Texas 75235. To whom requests for reprints should be addressed.

Received 1/22/82. Accepted 6/15/82.