Modulation of formation of tumor metastases by peritoneal macrophages elicited by various agents.

Abstract

We have studied the formation of experimental B16 melanoma metastases in the lungs of mice inoculated IV with tumoricidal or nontumoricidal peritoneal macrophages elicited by various agents. IV inoculation of peritoneal M phi elicited by Brewer's thioglycollate medium (TG-M phi) 1 day before the injection of B16 melanoma cells dramatically increased the number of metastatic foci in the lungs. NIH thioglycollate broth and proteose peptone each elicited a relatively low number of M phi, which were morphologically distinguishable from TG-M phi and did not influence the yield of B16 melanoma colonies in the lungs. Resident or C. pravum-elicited M phi also did not augment metastasis formation. TG-M phi became highly tumoricidal after IP stimulation with poly I:C. However, tumoricidal TG-M phi inoculated IV 1 day before IV inoculation of B16 melanoma cells did not have an antimetastatic effect. On the contrary, both tumoricidal and nontumoricidal TG-M phi augmented metastasis formation. Poly I:C treatment had a substantial antimetastatic effect in the normal mice, but not in mice with adoptively transferred TG-M phi. Histological analysis revealed that IV-inoculated TG-M phi (tumoricidal or nontumoricidal, either viable or disrupted) induced severe intravascular reaction in the lungs, but not in the liver or kidney. This reaction manifested in the aggregation of the various blood cells, preferentially neutrophils. These reactions were not observed after IV inoculation of PM phi or NIH TG-M phi. Intravascular inflammatory reactions induced by TG-M phi may be responsible for the augmentation of metastasis formation, partly by suppression of NK reactivity and mostly by the acceleration of the processes of tumor cell extravasation. These data may provide some insight into the failure to achieve systemic adoptive immunotherapy using activated peritoneal TG-M phi.