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Functional characterization of a stable, noncytolytic stage of macrophage activation in tumors
Abstract:
The state in which macrophages (Mphi) from regressing Moloney sarcomas could kill tumor target cells was a highly labile one which decayed rapidly in vitro. Thereafter, regressor Mphi were noncytolytic. Mphi from several different progressing sarcomas failed to kill, even when challenged with target cells immediately after explantation. Similarly, thioglycollate-induced peritoneal Mphi (TG-Mphi) did not kill. Noncytolygic Mphi derived either from progressing sarcomas or from long-term (up to 96 h) cultures of regressor Mphi were exquisitely sensitive to stimulation by bacterial lipopolysaccharide (LPS); picogram/milliliter amounts induced killing. Similar concentrations of LPS had no demonstrable effect on TG-Mphi. Thus, tumor Mphi generally appeared to have been primed in vivo, with those in regressing sarcomas having additionally acquired cytolytic activity. Inability of progressor Mphi to kill apparently stemmed from lack of, or failure to respond to, the signal needed in vivo to trigger cytolytic activity, rather than the total absence of activation.
Insights
Macrophages from regressing Moloney sarcomas can kill tumor cells but this ability is lost quickly in vitro. Bacterial lipopolysaccharide (LPS) can trigger killing in tumor-associated macrophages (TAMs).
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Macrophages (Mphi) play a critical role in tumor immunity.
- The cytotoxic potential of tumor-associated macrophages (TAMs) is variable and context-dependent.
- Understanding TAM activation is crucial for developing effective cancer immunotherapies.
Purpose of the Study:
- To investigate the cytotoxic state of macrophages from Moloney sarcomas.
- To determine the factors influencing macrophage (Mphi) cytolytic activity in vivo and in vitro.
- To identify signals that can restore or induce killing in non-cytolytic TAMs.
Main Methods:
- Explantation and in vitro culture of macrophages from regressing and progressing Moloney sarcomas.
- Assessment of macrophage (Mphi) cytotoxicity against tumor target cells.
- Stimulation of macrophages with bacterial lipopolysaccharide (LPS) to evaluate killing capacity.
Main Results:
- Macrophages from regressing sarcomas exhibited transient in vitro cytotoxicity that rapidly decayed.
- Macrophages from progressing sarcomas and long-term regressor cultures were non-cytolytic.
- Non-cytolytic tumor macrophages were highly sensitive to picogram/milliliter concentrations of LPS, inducing killing.
- Thioglycollate-induced peritoneal macrophages (TG-Mphi) did not exhibit LPS-induced killing.
Conclusions:
- Tumor-associated macrophages (TAMs) are generally primed in vivo.
- Macrophages in regressing sarcomas acquire cytolytic activity, which is labile.
- The inability of progressor TAMs to kill may result from a failure to respond to an in vivo triggering signal, not a lack of activation.