Phagocytosis, the ingestion of particulate matter, plays an essential role in the maintenance of tissue homeostasis. It serves as a first line of defense in the elimination of invading pathogens. Phagocytosis also prevents secondary necrosis and unwanted inflammation by efficiently recognizing and disposing of apoptotic bodies and debris. In addition, phagocytic clearance of malignant cells is fundamental in the innate immune surveillance for cancerous growth; indeed, suppression of phagocytosis facilitates tumor-mediated immune evasion. Given these essential functions, phagocytes reside in virtually all tissues of the body, where they constantly survey their surroundings for prey.
In their surveillance, phagocytes must rapidly distinguish harmful from healthy components by detecting features exposed on the surface of their putative targets. Features that trigger phagocytosis can be intrinsic to the target or facilitated by the deposition of soluble opsonins on the target. These ligands are called “eat me” signals as they engage phagocytic receptors that trigger extensive remodeling of the plasma membrane and of the actin cytoskeleton, culminating in the extension of pseudopods that surround and engulf the target.
In addition to scanning for “eat me” signals, phagocytes also recognize surface molecules that serve as “don’t eat me” signals. These include CD47, PD-L1, and CD24 that engage their cognate receptors SIRPα, PD-1, and Siglec-10, respectively, to exert an inhibitory effect on phagocytosis. When engaged, these inhibitory receptors arrest signaling pathways by recruiting otherwise cytosolic phosphatases that suppress phagocytic signaling. Certain tumors have found ways to usurp these mechanisms to support their growth. IgG-based biologics that target the “don’t eat me” pathways of cancerous lesions have been deployed with some success. Augmenting these responses would be advantageous. Since phagocytosis is a tunable and translationally impactful process, dependent on the features of the target and the microenvironment of the phagocyte, understanding the mechanisms that modulate receptor activation is of great importance.
We are interested in how pathogens and malignant cells avoid close contacts with immune cells by a glycocalyx barrier. Targeted removal of the tumour glycocalyx may unleash immune responses against it.