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

Abstract

The extent to which the functional heterogeneity of Mvarphis is dependent on the differentiation of functional sublineages remains unresolved. One alternative hypothesis proposes that Mvarphis 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 Mvarphis in chronic pathologies do not represent Mvarphi sublineages but rather, are mutable phenotypes sustained by chronic signaling from the pathological environment. Solid TAMvarphis 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 TAMvarphis in situ, reducing Mvarphi support of tumor growth and metastasis and enhancing Mvarphi proimmunogenic activities. Increased knowledge of how Mvarphi function is regulated and how polarized Mvarphis can be reprogrammed in situ will increase our ability to control Mvarphi function in a variety of pathological states, including cancer and chronic inflammatory disease.

Figure 1.

Functional categories of Mϕ function based on destructive or constructive activities. These two broad categories of Mϕs function less conflicted than the categories of inflammatory versus anti-inflammatory activities or “Th1 versus Th2” categories. However, they do not include many of the physiological activities displayed by tissue Mϕs.

Figure 2.

In situ reprogramming of TAMϕs by IL-12. Treatment of tumor-bearing mice alters the functional phenotype of Mϕs in peritoneum, spleen, and tumor-bearing organs, reducing production of tumor-supportive and/or immunosuppressive cytokines (A) and elevating the production of several potent inflammatory and proimmunogenic cytokines, such as IL-15 (B).