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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.
Insights
Thioglycollate-elicited macrophages (TG-M phi) significantly increased B16 melanoma lung metastases. These macrophages induced severe intravascular reactions, potentially hindering adoptive immunotherapy efficacy.
Area of Science:
- Immunology
- Cancer Metastasis
- Macrophage Biology
Background:
- Peritoneal macrophages play a role in immune responses and cancer progression.
- Understanding macrophage activation and their impact on metastasis is crucial for cancer therapy.
Purpose of the Study:
- To investigate the effect of different types of elicited peritoneal macrophages on B16 melanoma lung metastasis formation.
- To determine if tumoricidal activity of macrophages correlates with their antimetastatic potential.
- To elucidate the mechanisms underlying macrophage-mediated augmentation of metastasis.
Main Methods:
- In vivo study using mice inoculated with B16 melanoma cells.
- Elicitation of peritoneal macrophages using various agents (thioglycollate, proteose peptone, C. pravum).
- Intravenous (IV) inoculation of macrophages before tumor cell injection.
- Assessment of metastatic foci in the lungs.
- Histological analysis of lung, liver, and kidney tissues.
- In vitro activation of macrophages with poly I:C.
Main Results:
- IV inoculation of peritoneal macrophages elicited by Brewer's thioglycollate medium (TG-M phi) dramatically increased lung metastases.
- Macrophages elicited by NIH thioglycollate broth or proteose peptone did not influence metastasis.
- Tumoricidal TG-M phi did not exhibit an antimetastatic effect; instead, both tumoricidal and nontumoricidal TG-M phi augmented metastasis.
- IV-inoculated TG-M phi induced severe intravascular inflammatory reactions in the lungs, characterized by neutrophil aggregation.
- Poly I:C treatment showed an antimetastatic effect in normal mice but not in mice with transferred TG-M phi.
Conclusions:
- TG-M phi, regardless of their tumoricidal state, augment B16 melanoma lung metastasis formation.
- Intravascular inflammatory reactions induced by TG-M phi in the lungs are likely responsible for increased metastasis.
- These findings suggest that TG-M phi may suppress NK cell activity and accelerate tumor cell extravasation.
- The study provides insights into the potential failure of systemic adoptive immunotherapy using activated peritoneal TG-M phi.