Editors' ChoiceCancer

TAMing efferocytosis to fight tumors

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Science Translational Medicine  04 Mar 2020:
Vol. 12, Issue 533, eabb0795
DOI: 10.1126/scitranslmed.abb0795

Abstract

Preventing clearance of dying tumor cells elicits an inflammatory response by macrophages, supporting development of antitumor immunity in mice.

Cancer immunotherapies are continuing to revolutionize patient care, providing some of the greatest improvements in clinical outcomes seen in decades. Yet, a limited number of patients respond to treatment, motivating development of strategies that further address the immune suppressive tumor environment. In a recent report, Zhou et al. develop an approach to bolster the immune response against tumors by blocking clearance of dying tumor cells by tumor-associated macrophages (TAMs).

Within tumors and throughout the body, dying cells are cleared by macrophages. These phagocytic immune cells recognize dying cells through a myriad of cell-surface receptors, including MER proto-oncogene tyrosine kinase (MerTK). Efferocytosis typically occurs early in the process of the target cell’s demise, before release of cellular contents (for example, cell fragments or DNA) that can act as inflammatory stimulants. Clearance therefore prevents inflammation and contributes to immune tolerance of solid tumors. To address this issue, the team developed an antibody that blocked MerTK receptors on macrophages. In tumor-bearing mice, MerTK inhibition increased accumulation of dead or dying cells in the tumor. These dead cells released cell fragments, including increased quantities of cell-free DNA. Interestingly, free DNA did not activate macrophages directly. Instead, free DNA generated tumor cell–derived cGAMP (a potent inflammatory stimulant), which subsequently activated the STING pathway in macrophages, provoking them to further elicit an adaptive immune response. Although MerTK inhibition alone was ineffective against large established tumors, combination therapies were highly effective, including the addition of anti-PD1—to activate the adaptive T cell response—and cytotoxic chemotherapy—to increase the number of dying tumor cells.

There is a growing appreciation that innate immune activation is essential for the induction of an adaptive immune response. In this instance, MerTK-mediated clearance of dying cells is an innate immune checkpoint, preventing an inflammatory macrophage response. MerTK inhibition removes the brakes, allowing macrophages to produce inflammatory signals which further evoke antitumor immunity. Numerous clinical trials are already investigating innate immune agonists in combination with existing checkpoint inhibitors, including STING and TLR7/8 agonists: NCT03172936, NCT03906526, NCT03301896. Emerging therapeutic approaches should similarly seek to address both arms of the immune system—overcoming the intrinsically immunosuppressive tumor environment and simultaneously fueling a potent adaptive response.

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