Macrophages as mediators of tumor immunosurveillance

Abstract

Tumor immunosurveillance is a well-established mechanism for regulation of tumor growth. In this regard, most studies have focused on the role of T- and NK-cells as the critical immune effector cells. However, macrophages play a major role in the recognition and clearance of foreign, aged, and damaged cells. Macrophage phagocytosis is negatively regulated via the receptor SIRPalpha upon binding to CD47, a ubiquitously expressed protein. We recently showed that CD47 is up-regulated in myeloid leukemia and migrating hematopoietic progenitors, and that the level of protein expression correlates with the ability to evade phagocytosis. These results implicate macrophages in the immunosurveillance of hematopoietic cells and leukemias. The ability of macrophages to phagocytose tumor cells might be exploited therapeutically by blocking the CD47-SIRPalpha interaction.

Figure 1

Hypothetical model of pro- and anti-phagocytic signaling in hematopoiesis. A) At steady state, CD47 signal strength is sufficient to overcome low pro-phagocytic ligand expression. B) When stem or progenitor cells undergo apoptosis, they increase expression of pro-phagocytic signals and phosphatidylserine, as well as decrease CD47, which allows for highly efficient phagocytosis. C) After administration of LPS, macrophages down-regulate SIRPα, which lowers the threshold for phagocytosis, allowing pro-phagocytic signals to dominate. D) The normal physiological response to inflammatory mediators is up-regulation of CD47 on hematopoietic cells, which allows lowered SIRPα on activated macrophages to be more efficiently engaged, thus preventing phagocytosis. E) Pre-leukemic clones may upregulate pro-phagocytic ligands, marking them for destruction via phagocytosis. F) Via natural selection, clones high for CD47 are selected over time, allowing these escape variants to survive. G) Blocking CD47 on leukemic clones masks an anti-phagocytic signal, allowing pro-phagocytic signals to dominate.

Figure 2

Two possible models for selection of CD47 high-expressing leukemic clones A) In the first model, tumor growth incites a localized inflammatory reaction that causes macrophage activation and SIRPα down-regulation. Only those clones that highly express CD47 survive in this toxic mileu. B) In the second model, pro-phagocytic ligands are up-regulated on early leukemic clones, marking them for phagocytosis. Over time, clones that are high expressers of CD47 are enriched because they are immune to clearance by macrophages.