LC3-Associated Phagocytosis (LAP): A Potentially Influential Mediator of Efferocytosis-Related Tumor Progression and Aggressiveness

Abstract

One aim of cancer therapies is to induce apoptosis of tumor cells. Efficient removal of the apoptotic cells requires coordinated efforts between the processes of efferocytosis and LC3-associated phagocytosis (LAP). However, this activity has also been shown to produce anti-inflammatory and immunosuppressive signals that can be utilized by live tumor cells to evade immune defense mechanisms, resulting in tumor progression and aggressiveness. In the absence of LAP, mice exhibit suppressed tumor growth during efferocytosis, while LAP-sufficient mice show enhanced tumor progression. Little is known about how LAP or its regulators directly affect efferocytosis, tumor growth and treatment responses, and identifying the mechanisms involved has the potential to lead to the discovery of novel approaches to target cancer cells. Also incompletely understood is the direct effect of apoptotic cancer cells on LAP. This is particularly important as induction of apoptosis by current cytotoxic cancer therapies can potentially stimulate LAP following efferocytosis. Herein, we highlight the current understanding of the role of LAP and its relationship with efferocytosis in the tumor microenvironment with a view to presenting novel therapeutic strategies.

LAPped in Proof: LC3‐Associated Phagocytosis and the Arms Race Against Bacterial Pathogens

“…It is thought that the immunosuppressive signaling networks associated with LAP could be hijacked by developing cancer cells to bypass the immune response, thereby promoting their progression and metastatic potential. The implications of this have been reviewed elsewhere (Asare et al, 2020).…”

The p53 family member p73 in the regulation of cell stress response

“…Bax oligomerization and formation of pores on the outer mitochondrial membrane leads to the release of cytochrome C in the cytoplasm, apoptosome assembly and subsequent caspase-mediated cleavage of cellular proteins [ 251 ]. At the late stages, apoptosis culminates in DNA fragmentation [ 252 ] and induction of phagocytosis [ 253 ].…”

MERTK-Mediated LC3-Associated Phagocytosis (LAP) of Apoptotic Substrates in Blood-Separated Tissues: Retina, Testis, Ovarian Follicles

“…Two possible explanations of this phenomenon have been proposed, the first of them is based on the involvement of TAM receptors in the LAP-mediated mechanism of apoptotic substrate elimination. Indeed, the similar SLE-like phenotype was described for mice lacking one or several components of the LAP pathway, triggered (among others) by the activation of TAM receptors [176,177]. Remarkably, dying cells, injected into LAPdeficient animals, are ingested by immune cells, but not efficiently degraded, and trigger acute elevation of pro-inflammatory cytokines.…”