The Physiological and Therapeutic Role of CD47 in Macrophage Function and Cancer.

Background: Immunotherapy is an emerging strategy in cancer therapeutics aimed at modulating the immune system to inhibit pro-tumor pathways and increase a tumor's sensitivity to chemotherapy. Several clinically approved immunotherapy treatments, such as monoclonal antibody treatments, have been successful in solid tumors such as breast, colorectal, and pancreatic. However, an outstanding challenge of these strategies is tumor cell resistance. One target of interest for immune cell modulation is targeting macrophages that enter the tumor microenvironment. More specifically, an immune checkpoint of interest is CD47. CD47 is a transmembrane protein that inhibits phagocytic activity by acting as a "don't eat me" signal. In both mice and humans, healthy cells can express CD47, while solid malignancies like colorectal and breast cancer express it most strongly.

Methods: Analysis of literature data on the physiological and functional roles of tissue-resident macrophages, along with the structure and mechanisms of action of the CD47 pathway was explored. We also explored how CD47 can influence different aspects of the tumor microenvironment (i.e. cellular metabolism and hypoxia) in addition to current clinical strategies and challenges associated with targeting CD47.

Results: Overall, it was discovered that CD47 is overexpressed in a variety of cancer types in addition to normal tissue, making it a promising treatment regimen to enhance the capability of macrophages to phagocytose tumor cells. However, treatment efficacy is varied in pre-clinical and clinical models due to various challenges such as off-target effects.

Conclusion: This review emphasizes the diverse functionality of macrophages in normal and cancerous tissue, while also emphasizing the importance of macrophage targeting and their clinical significance.