Suppression of the generation of lymphokine-activated killer (LAK) cells by serum-free supernatants of in vitro maintained tumour cell lines

Abstract

Summary Serum-free supernatants from in vitro maintained gastrointestinal cancer and melanoma cell lines inhibit the generation of lymphokine (IL-2) activated killer (LAK) Lafreniere et al., 1985;Mule et al., 1986b;Rosenberg et al., 1986). Unfortunately this experience is not paralleled by the clinical application of such an approach where some 60% of patients with metastatic disease fail to respond to this therapy West et al., 1987;Topalian et al., 1988). Similarly, treatment with IL-2 alone appears to be ineffective (Lotze et al., 1986) despite the fact that many human tumours are infiltrated by host mononuclear cells which might become cytotoxic following exposure to IL-2 in vivo (Svennevig et al., 1984;Cozzolino et al., 1986).Prompted by the observations that both IL-2 production and LAK cell generation were impaired with patients with tumours which had extended beyond local confines (Monson et al., 1986(Monson et al., , 1987, we have previously shown that the presence of low numbers of some cell-line derived tumour cells was found to potently inhibit LAK cell generation in vitro (Guillou et al., 1989). A number of reports have demonstrated that supernatants derived from tumour cell lines can inhibit lymphocyte proliferation and cytokine production (Werkmeister et al., 1980; Meischner et al., 1986;Ebert et al., 1987;Pommier et al., 1987;Farram et al., 1982;Hersey et al., 1983). However, the effects of these supernatants on the generation of cytotoxic responses has rarely been examined (Cozzolino et al., 1987

Suppression of lymphokine‐activated killer cell cytotoxicity by a soluble factor produced by squamous tumors of the head and neck

“…The colon cancer cell line HT29 produces reversible suppression of T-cell proliferation; however, this effect is mediated by a factor with an apparent molecular weight of 56 kd," A suppressive factor derived from adult T-cell leukemia, with a similar molecular weight as SCIF, also inhibits T-cell proliferation, but unlike the SCIF, it is heat-stable at 60°C. 34 Recently, suppression of LAK cytotoxicity by supernatants from in vitro maintained gastrointestinal cancer and melanoma cell lines has been described. 35 The inhibitory factor has a molecular weight of >25 kd: however, unlike the SCIF, it is stable at 56°C and produces inhibition of LAK generation only if present within the first 48 hours of culture.…”

Comparison of transforming growth factor β and a human tumour-derived suppressor factor

“…Despite the almost universal success of IL-2 therapy in animal models, patients with advanced malignant disease have only a modest response rate of approximately 20%-30% [21]. Several mechanisms have been proposed for the clinical failure of immunotherapy including increased resistance of cytokinetreated tumour cells to cytolysis [4] and the production of immunosuppressive factors by tumour cells [10].…”

“…The immunosuppressive component is actively produced by some tumour cell lines, but not others, and there is concordance between the ability of intact tumour cells and their serum-free supernatants to inhibit the generation of LAK cells [10]. The tumour-derived suppressor factor (TDSF) was immunosuppressive in a dose/response manner and maximal suppression was obtained when TDSF was added at the initiation of lymphocyte activation with interleukin-2 [ 10].…”

Prothymosin α restores depressed allogeneic cell‐mediated lympholysis and natural‐killer‐cell activity in patients with cancer

“…The NK-cell activity expressed by MNC from patients with cancer has been consistently reported to be abnormally low (Balch et al, 1983). Production of PGE2 by tumor-activated monocytes (Unger et al, 1983), suppressor factors released by tumor cells (Guillon et al, 1989), and a failure of patients' lymphocytes to generate adequate levels of IL-2 (Monson et al, 1986;Anastasopoulos et al, 1992) have been considered at least partly responsible for the decreased NK activity.…”