Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages

The extent to which the functional heterogeneity of M phi s is dependent on the differentiation of functional sublineages remains unresolved. One alternative hypothesis proposes that M phi s are functionally plastic cells, which are capable of altering their functional activities progressively in response to progressively changing signaling molecules generated in their microenvironment. This functional plasticity hypothesis predicts that the functionally polarized M phi s in chronic pathologies do not represent M phi sublineages but rather, are mutable phenotypes sustained by chronic signaling from the pathological environment. Solid TAM phi s are chronically polarized to provide activities that support tumor growth and metastasis and suppress adaptive immune responses. In support of the functional plasticity hypothesis, administration of slow-release microsphere-encapsulated IL-12 successfully reprogrammed TAM phi s in situ, reducing M phi support of tumor growth and metastasis and enhancing M phi proimmunogenic activities. Increased knowledge of how M phi function is regulated and how polarized M phi s can be reprogrammed in situ will increase our ability to control M phi function in a variety of pathological states, including cancer and chronic inflammatory disease. J. Leukoc. Biol. 86: 1105-1109; 2009.