Target cells are sensitized for cytotoxic T‐lymphocyte‐mediated destruction by estradiol and tamoxifen

Abstract

The effect of estradiol (E2) and tamoxifen (TX) on cytotoxic T-lymphocyte (CTL)-mediated target-cell lysis was studied. CTL was generated in mixed cultures of rat spleen cells, using female Fischer 344 rat cells as responders and female Wistar rat cells or Nb2 rat lymphoma cells as stimulators. Concanavalin-Astimulated Wistar lymphoblasts or Nb2 cells were used as targets. CTL harvested on day 5 exerted 1645% cytotoxicity when used at 1:12-1:50 targekeffector cell ratios. Day-6 CTL had no cytotoxic activity. Treatment of target cells with either TX or E2, or both, at I-pM concentrations for 4 hr prior to cytotoxicity testing raised the target-cell killing to loo%. Highly significant enhancement of cytotoxicity was also observed when the drugs were used at 100-, lo-, or I-nM concentrations.Treatment of effector cells under similar conditions led to inhibition of cytotoxicity at I -pM concentration, some enhancement at I00 nM and no effect at 10 and I nM. When treated target and effector cells were combined, the amplification of target-cell lysis was similar in magnitude to that seen in tests with treated targets only. Drug treatment of target cells had no influence on their resistance to lysis in hypotonic solutions or on total and spontaneous release. The inhibition of DNA and protein synthesis in target cells interfered with both basal cytolysis and drug-induced enhancement. The release of the nuclear label, [3H]-thymidine, from Nb2 targets by CTL, was also enhanced by target treatment with TX. These results illustrate that CTL-mediated cytotoxicity is amplified by physiological concentrations (I and 10 nM) of E2 and equimolar concentrations of TX. o 1994 Wiley-Liss, Inc.It is well established that sex hormones influence various features of the immune system, although their mechanism(s) of action has not yet been established with certainty. A direct action on mature lymphoid cells, as well as an indirect action influencing bone-marrow or thymus function, have been proposed as underlying mechanisms. Estradiol is known to enhance humoral immune responses and to suppress cellmediated immunity. The immunological superiority of females and their proneness to autoimmune disease is often attributed to estradiol (Grossman, 1985;Nelson and Steinberg, 1987).The non-steroidal anti-estrogenic agent tamoxifen (TX) is widely applied in the treatment of breast carcinomas and of some other sex-hormone-dependent tumors (Lerner and Jordan, 1990). Although there is considerable evidence to support the hypothesis that this drug inhibits tumor growth by blocking the stimulatory effect of estradiol at the receptor level, there is a good indication that patients with estrogen-receptornegative tumors also benefit from TX treatment (Baral ef al., 1987). The mechanism of inhibition by TX of estrogen-receptornegative tumors is unknown at the present time.Recent studies have revealed that TX is a potent immunomodulatory agent (reviewed by Baral et al., 1994). Therefore, it is possible that immune reactions play a role in the beneficial ef...

Immunotherapy of Cancer—A Historical Note

“…This was a dual effect by estradiol and tamoxifen. Tamoxifen apparently increased tumor immunity by this dual action [17]. Similar dual enhancement was observed also by lymphokine activated killer cells [18].…”

Suppression of Lymphocyte Mitogenesis by Tamoxifen: Studies on Protein Kinase C, Calmodulin and Calcium

“…In contrast, TX potentiated the lysis of target cells by natural killer, lymphocyte-activated killer and cytotoxic T lymphocyte (CTL) effector cells. This amplification was due to the sensitization of target cells for cytolysis, which is not mediated by classical estrogen receptors [11][12][13][14].…”

Molecular Mechanisms of Estrogen and Antiestrogen Resistance

“…The stable ICI 182,780-resistant population was designated MCF-7/LCC9. MCF-7/LCC9 cells are resistant to ICI 182,780 in vitro and in vivo) 49 Our data indicate that these cells exhibit cross-resistance to tamoxifen, even though the cells have not been exposed to a triphenylethylene antiestrogen. If correct, this pattern of in vitro resistance would suggest that patients may be better served if treated initially with tamoxifen and subsequently with a steroidal antiestrogen, rather than vice versa.…”

“…Amplification and/or overexpression of erbB2 has been shown to correlate with poor clinical outcome in lymph-node positive patients, but the prognostic significance of erbB2 in node-negative disease, as seen here in the left breast lesion, is controversial [48]. ErbB2 expression has been associated with poor clinical outcome in a certain subset of node-negative patients; those with small, ER-positive, predominantly invasive tumors [49]. The lack of expression of erbB2 in the metastasic bone lesion supports the underlying assumption that it arose from the erbB2 negative, invasive lesion on the right, rather than from the DCIS on the left.…”

“…Accumulation of NK cells in tumors was temporally associated with a clinical spontaneous remission in a patient with metastatic breast carcinoma (47). Other reports (48)(49)(50) indicate that pharmacologically achievable concentrations of tamoxifen enhance immune cytolysis of tumor targets mediated by LAK cells and cytotoxic T cells. Overall and except for the observation by Gottardis et al (43), these reports and our results are consistent with the hypothesis that host immune function may play a role in the antitumor effect of triphenylethylene antiestrogens, independent of the ER status of the tumor cell target.…”