Yan Minhong's team revealed a new tumor immune escape mechanism.

The occurrence and development of tumors depend on a variety of mechanisms, one of which is immune escape avoidance recognition and elimination.although blocking T-cell immunosuppressive pathways, such as PD-1 / PD-L1 inhibitors, can activate the adaptive immune system and make unprecedented progress in clinical practice, the overall response rate of the treatment population is still not high.one of the potential important factors is that the innate immune system, as another important branch of the immune system, has not been fully mobilized, which limits the recognition and inhibition of tumor by the immune system.MERTK is a receptor expressed on macrophages and can promote phagocytosis.during cell apoptosis, phosphatidylserine (ptdser) is exposed to the cell surface. MERTK mediates the rapid phagocytosis and clearance of apoptotic cells by macrophages through the recognition of ptdser by the bridge molecule Gas6 or protein S. this process is called efferocytosis.timely and efficient clearance of apoptotic cells prevents damage associated molecular patterns (damps) from being released into the tissue microenvironment, ensuring the so-called "immune silence", which is essential for ensuring the homeostasis of normal tissues in vivo.similarly, in the process of tumorigenesis and development, tumor is likely to use this mechanism to clear apoptotic tumor cells with the help of tumor associated macrophages (TAMs), so as to prevent the immune system from recognizing the tumor, and then weaken the immune response to tumor.on February 11, 2020, the team of Dr. Minhong Yan of Genentech published an article entitled "blockade of the pharmacokinetic receiver MERTK on tumor associated macrophases strengths P2X7R dependent sting activation by tumor derived cgamp" online in immunity magazine.the researchers of Genetech used specific functional antibodies to target the inhibition of MERTK on TAMs, revealing the mechanism and application potential of enhancing tumor immunogenicity and anti-tumor immunity by blocking MERTK.at the same time, this study elucidated a new activation mode of sting signaling pathway in immune cells in tumor microenvironment.the authors first used a series of experiments in vivo and in vitro to verify the effective function of MERTK antibody in blocking intercellular burial.through homologous mouse tumor experiment, the authors found that MERTK antibody treatment could lead to the accumulation of apoptotic cells, and more circulating tumor DNA (ctDNA) and host free DNA (cfdna) from damaged or dead cells could be detected in plasma of treated mice, indicating that MERTK antibody can effectively inhibit the clearance of apoptotic cells in tumor microenvironment.in further studies, the authors found that blocking MERTK inhibited tumor growth, and MERTK antibody significantly enhanced the efficacy of PD-1 antibody or PD-L1 antibody in different mouse tumor models.when gemcitabine, PD-1 antibody and MERTK antibody were used in combination, all the treated tumors almost disappeared, and the response rate was 100%.next, the authors conducted a series of experiments to further explore the mechanism of blocking the antitumor effect of MERTK.by RNA SEQ analysis of TAMs, the authors found that blocking MERTK resulted in a significant increase in IFN I response characteristics, and this change was limited to tumor lesions.blocking the type I interferon signaling pathway leads to the complete loss of anti-tumor effect of MERTK antibody, which indicates that inducing the production of type I interferon is a key mechanism for the therapeutic effect of MERTK antibody. interferon type I is a very important cytokine regulating immune response, which can promote the maturation and function of antigen-presenting cells and enhance the activation of T cells. indeed, the authors found that MERTK antibody increased the clonality and frequency of tumor infiltrating CD8 + T cells and increased the number of tumor specific CD8 + T cells. in addition, the elimination of CD8 + T cells makes MERTK antibody completely lose its anti-tumor effect. CGAs sting signaling pathway is an important way to mediate the production of type I interferon. Therefore, how to enhance the CGAs sting signaling pathway has become a hot spot in the research and development of tumor immunotherapy. however, it is still uncertain how this signaling pathway is activated in tumors. the authors found that MERTK antibody was completely ineffective in sting deficient mice, but still produced type I interferon response and antitumor effect in CGAs knockout mice. the authors also found that CGAs in tumor cells is crucial for the role of MERTK antibody. These results suggest that the activation of sting in immune cells depends on CGAs in tumor cells rather than CGAs in immune cells. CGAs is activated by recognizing double stranded DNA in the cytoplasm, and cgamp is synthesized using ATP and GPT as substrates. cgamp, as the second messenger, binds and activates sting to induce the expression of interferon type I. so the question is how does cgamp produced by tumor cells reach the cytoplasm of immune cells and activate sting? The authors suggest that inhibition of the clearance of apoptotic tumor cells by MERTK antibody can increase the release of ATP and cgamp into the tumor microenvironment. ATP opens the ATP gated P2X7R ion channel on TAMs, and promotes cgamp to enter the cytoplasm of TAMs through P2X7R channel to activate sting and promote the production of type I interferon. the authors conducted a series of case studies using P2X7R knockout mice, P2X7R small molecule inhibitors, or tumor cells overexpressing CD39, an enzyme that degrades extracellular ATP. in conclusion, this study reveals a novel mechanism of tumor immune escape: TAMs inhibit the release of tumor risk signals (such as ATP and cgamp) and the consequent innate immune perception through MERTK dependent intercalation. the innate immune checkpoint of targeted inhibition of MERTK provides a new opportunity for enhancing tumor immunotherapy. at the same time, the newly discovered atp-p2x7r-cgamp-sting mechanism in immune cells provides a new way to design a new generation of sting agonists. the first authors of the article are Yi Zhou and Mingjian Fei. original link: