Lymphotoxin enhances the susceptibility of neoplastic and preneoplastic cells to natural killer cell mediated destruction

Abstract

Treatment of neoplastic guinea-pig cells for 1-14 days with 300 units of guinea-pig lymphotoxin/ml medium enhanced 2- to 5-fold their susceptibility to natural killer (NK) cell-mediated cytotoxicity as measured by 4 h 51Cr and 72 h [3H]-thymidine-release assays. The NK susceptibility of human neoplastic and guinea-pig non-neoplastic cells refractory to guinea-pig lymphotoxin growth-inhibitory activity was unchanged after lymphotoxin treatment. Lymphotoxin preparations were free of detectable interferon and the enhancing activity copurified with lymphotoxin during diafiltration and isoelectric focusing. Treatment of NK cells with lymphotoxin preparations also augmented NK-mediated lysis but that activity did not copurify with lymphotoxin. As with neoplastic cells, lymphotoxin-sensitive preneoplastic cells previously treated with ultraviolet light, a chemical carcinogen, or carcinogen and the tumor-promoting agent tetradecanoylphorbol-acetate also exhibited lymphotoxin enhancement to NK-cell destruction. Thus, the immunologic hormone lymphotoxin enhances the susceptibility of lymphotoxin-sensitive cells to NK-cell destruction, indicating that these two natural immune mediators, lymphotoxin and NK cells, have the potential in concert to regulate carcinogenesis and neoplastic growth.

Control of the carcinogenic potential of 99mTechnetium by the immunologic hormone lymphotoxin

“…It is distributed and bound by appropriate cell surface sites, where it exerts its anticarcinogenic action. Both increased synthesis of membrane glycoproteins [16] and enhancement of preneoplastic cells to natural killer cell-mediated cytotoxicity [25] have been observed in lymphotoxin-treated cells. These may be possible direct or indirect mechanisms whereby lymphotoxin exerts its anticarcinogenic action.…”

“…The natural immunologic hormones may provide new immunopharmacologic agents for the prevention of cancer [9,12,27]. One of the immunologic hormones, lymphotoxin, is anticarcinogenic [9,12,27] and is active during several stages of carcinogenesis [6,12,14,25,27]. The anticarcinogenic activity Reprint requests should be addressed to 3.…”

“…Lymphotoxin induces the synthesis of large-molecular-weight membrane glycoproteins in normal cells which accompanies a lymphotoxin-induced state of resistance to carcinogenesis [6,16]. Preneoplastic cells, moreover, can also be inhibited by lymphotoxin, either by a direct growth-inhibitory action of lymphotoxin or indirectly by enhancing the susceptibility of the cells to natural killer cell-mediated cytotoxicity [25].…”

Lymphotoxin amplification of tumor growth inhibition is specific for natural killer cells but not for macrophages

“…One lytic unit is defined as the number of leukocytes causing 30 % specific ( 3H)-release from the 104C1 target cells (Ransom and Evans, 1982).…”

“…Lymphotoxin is preferentially cytotoxic via cytolytic or cytostatic mechanisms for malignant cells (Rundell and Evans, 1981;Evans and Heinbaugh, 1982), is anticarcinogenic in vitro (Evans and DiPaolo, 1981) and in vivo (Ransom et al, 1982a), and enhances the susceptibility of preneoplastic and malignant cells to natural killer (NK)-cell-mediated cytotoxicity in vitro (Ransom and Evans, 1982;Evans, 1983). Enhancement of NK cell cytotoxicity is restricted to cells susceptible to the cytostatic action of lymphotoxin, i.e., normal cells are unaffected.…”