During the past several decades, it has become increasingly clear that there is a complicated relationship between a tumor and the patient’s immune system. Although the genetic and epigenetic changes that fuel cancer development create foreign antigens that should trigger an immune response, one of the hallmarks of cancer is its ability to evade this immune recognition.
The immuno-oncology field has blossomed as researchers have gotten a better grasp of the mechanisms that cancer cells use to suppress the antitumor immune response.
The dominant strategy thus far has been to activate T cells, the central mediators of the adaptive immune response. This approach is antigen specific, involves memory recall, and could in theory have long-lasting therapeutic benefit.
Yet there are 2 arms to the immune system that act in concert with one another and evidence is building that the second arm—the innate immune response—is also likely to be important.
As a result, researchers and pharmaceutical companies, seeking to carve out new niches in the immuno-oncology field, are looking to the major player in the innate immune response: the macrophages.
A particularly promising therapeutic target in this area is the CD47 protein, dubbed the “don’t eat me” signal for its role in inhibiting the phagocytic activity of macrophages and seemingly exploited by cancer cells to make them appear as normal cells to the innate immune response.
Exploration of CD47-targeting antibodies in preclinical and early clinical trials is beginning to scratch at the surface of the hidden complexities of this nearly ubiquitously expressed protein. It has also revealed the likely complementary role of CD47-targeted therapies to both other immunotherapies and targeted therapies, which could prove beneficial in rationally designed combination therapy.
The Other Arm of the Immune Response
Tumors clearly engage the cells of the innate immune response. Macrophages are among the most abundant normal cells found in the tumor microenvironment and evidence suggests that they are manipulated by cancer cells to become protumoral.
Furthermore, there is crosstalk between the innate and adaptive arms since macrophages and other phagocytic cells can present foreign antigens to T cells, triggering an adaptive immune response.
It is becoming increasingly clear that cancer cells have to sneak past the effector cells of both the adaptive and innate immune response to avoid destruction and that the innate immune response plays an important role—possibly, a therapeutically complementary role—in cancer development and progression.
Macrophages are the key effectors of the innate immune response and their primary function is to patrol the body in search of damaged, old, or foreign cells, and clear them from the body via phagocytosis in order to maintain cellular homeostasis.
Phagocytosis appears to be regulated by a delicate balance in the expression of cell-surface proteins that act as either “eat me” or “don’t eat me” signals to phagocytic effectors. Similar to T-cell activation, switching on macrophages also appears to be a 2-step process that requires both an upregulation of the “eat me” signals and a downregulation of the “don’t eat me” signals.
That is where CD47, the cluster of differentiation 47 protein (also known as integrin-associated protein), comes into focus.
“Don’t Eat Me”
CD47 is a membrane-spanning protein that belongs to the immunoglobulin superfamily and is expressed on almost every cell in the body. It has become best known for its pivotal role in regulating phagocytosis, thus earning it the moniker of being the “don’t eat me” signal.
In its phagocytic role, CD47 binds to signal regulatory protein alpha (SIRPα), another member of the immunoglobulin superfamily that is expressed on the surface of macrophages, as well as other phagocytic cells. The SIRPα protein consists of 3 immunoglobulin–like domains that protrude outside the cell, a portion that crosses the cell membrane, and a tail section that resides inside the cell and contains 4 immunoreceptor tyrosine-based inhibitory motifs (ITIMs).
By binding to one of SIRPα’s extracellular domains, CD47 triggers phosphorylation of the intracellular ITIMs, transmitting the signal through the cell membrane of the macrophage. This drives the recruitment and activation of 2 phosphatase enzymes, SHP1 and SHP2, and one of the downstream effects of this is the inhibition of myosin IIA accumulation at the phagocytic synapse, which ultimately suppresses phagocytosis.