Role of membrane lipids in the immunological killing of tumor cells: II. Effector cell lipids

Abstract

Peritoneal macrophages (M phi) from mice become cytotoxic after incubation in lymphokine (LK)-rich supernatants of antigen-stimulated spleen cell cultures. Tumoricidal activity is evident with M phi treated with LK for 4 hr, becomes maximal after 8-12 hr incubation and decreases to control levels by 24-36 hr. To gain insight into LK-induced functional changes, the lipid composition of M phi cultured with LK for 0-36 hr was analyzed by high pressure liquid chromatography. LK induced marked changes in M phi lipid composition: cellular content of cholesterol (CHOL) and polyunsaturated fatty acids increased 2- to 3-fold after 8 hr when the cells showed maximal tumoricidal activity. Cellular lipid and fatty acid content returned to control levels by 24 hr when the M phi had lost tumoricidal activity. These changes were not observed with equal numbers of M phi cultured in control supernatants. To analyze further the role of CHOL and unsaturated fatty acids in M phi tumor cytotoxicity, M phi were enriched in CHOL or linolenic acid (18:3) and tested for their ability to kill 1023 tumor cells. Within 1 hr of culture, M phi showed a 3- to 4-fold increase in CHOL or 18:3 content. 18:3-enriched cells were markedly tumoricidal, whereas controls cultured in delipidized medium alone or enriched with saturated fatty acids were cytotoxic. CHOL-enriched M phi were not tumoricidal; indeed, these cells were inhibited in their killing after treatment with LK compared to M phi cultured in delipidized medium with LK alone. These results suggest that UFA aids, whereas CHOL negates, expression of M phi tumor cytotoxicity.