Cancer immunotherapy is continuing to revolutionize the means of patient care, bringing hope and good news to patients. However, only a minority of patients respond to treatment, which drives the development of strategies to further address the immunosuppressive tumor environment. In a recent report, Zhou et al developed a method to enhance the immune response to tumors by preventing tumor-associated macrophages (TAMs) from removing dying tumor cells.
In tumors and throughout the body, dead cells are cleared by macrophages. These phagocytic immune cells recognize dead cells through a myriad of cell surface receptors, including the MER proto-oncogene tyrosine kinase (MerTK). Burial usually occurs early in target cell death and can act as an inflammatory stimulus before the release of cellular contents (e.g., cellular debris or DNA). Removal of preventable inflammation therefore contributes to immune tolerance in solid tumors.
To address this issue, the team developed an antibody that can block MerTK receptors on macrophages. In tumor-bearing mice, inhibition of MerTK increased the accumulation of dead or dying cells in the tumor. These dead cells release cellular debris, including large amounts of free DNA. Interestingly, free DNA did not directly activate macrophages. In contrast, free DNA derived from tumor cells produces cGAMP (a potent inflammatory stimulus), which subsequently activates the STING pathway in macrophages, further provoking them to induce adaptive immune responses. While MerTK inhibition alone is not effective against established large tumors, the combination is highly effective and includes the addition of anti-PD-1 to activate adaptive T cell responses and cytotoxic chemotherapy to increase the number of dead tumor cells.
It is increasingly recognized that innate immune activation is key to the induction of adaptive immune responses. In this context, MerTK-mediated clearance of dead cells is a natural immune checkpoint that prevents the response of inflammatory macrophages. MerTK inhibition eliminates the inhibition, allowing macrophages to generate inflammatory signals that further provoke antitumor immunity. A number of clinical trials have been investigating the combination of innate immune agonists with existing checkpoint inhibitors, including STING and TLR7/8 agonists: NCT03172936, NCT03906526, NCT03301896. Emerging treatments should similarly seek to address two branches of the immune system—overcoming the intrinsic immunosuppressive tumor environment while eliciting a robust adaptive response.