Science: great progress! The activation of RIG-I is very important to the antitumor effect of immunocheckpoint blocking

September 21, 2019 news / bioin / - -- targeting immune checkpoints such as CTLA-4 or PD-1 has been proved to be an effective tumor therapy Double inhibition of CTLA-4 pathway and PD-1 pathway showed particularly strong clinical response in different malignant tumors, including melanoma, renal cancer and non-small cell lung cancer However, there are significant differences in clinical responses between patients, and there is still limited understanding of the underlying mechanisms Several factors have been proposed to predict the therapeutic response to immune checkpoint blockade (ICB), including tumor mutation load, expression and diversity of major histocompatibility complex (MHC) molecules, tumor microenvironment infiltrated by T cells, composition of intestinal flora and lack of tumor immunosuppressive pathway In general, immunocheckpoint blockade is considered to reactivate tumor antigen-specific T cells Interferon-i (IFN-I) is an important factor in the production of this anti-tumor T cell response, because it promotes the accumulation of CD8 α + dendritic cells in the tumor and the cross activation of antigen-specific cytotoxic T cells to fight against the growing tumor, which eventually leads to tumor regression Therefore, the activation of IFN-I system around the tumor is related to the accumulation of CTL in the tumor and the spontaneous regression of primary mouse melanoma The characteristics of IFN-I gene in a large number of tumor samples are related to the favorable clinical response of melanoma patients to the blocking of immune checkpoint In view of ifn-1 induction pathway in tumor microenvironment, recent studies have revealed that cytoplasmic nucleic acid sensing receptor system has made an important contribution Although these innate immune receptors are often expressed in tumor cells, their role in anti-tumor immune response is mainly realized in the host bone marrow cells In particular, the CGAs / sting pathway in dendritic cells is associated with tumor rejection during immune checkpoint blockade and tumor immune monitoring induced by radiotherapy CGAs / sting is a cytoplasmic pattern recognition receptor system, which can recognize and indicate the existence of abnormal cytoplasmic double stranded DNA (dsDNA) under various conditions (including apoptosis, necrosis and DNA pathogen replication) In dendritic cells, sting can be activated by DNA from dying cancer cells (this can be enhanced by genotoxic stress during radiotherapy or chemotherapy), thus inducing high levels of ifn-1, which can promote the optimal cross activation of T cells and effective anti-tumor immune response As another important cytoplasmic nucleic acid sensing protein, RNA receptor RIG-I (encoded by gene ddx58) is also related to antitumor immune response RIG-I mainly detected double stranded 5 '- triphosphate RNA (3prna) during virus or bacterial infection Once combined with the ligands in bone marrow cells, RIG-I will recruit a adaptor protein called mitochondrial antiviral signaling protein (MAVs) to induce the production of pro-inflammatory cytokines and IFN-I, as well as the activation of ASC dependent inflammatory bodies, leading to a variety of innate and adaptive immune responses The activation of RIG-I pathway in bone marrow cells can induce ifn-1-dependent natural killer cell activation and metastasis regression from primary melanoma CGAs / sting and RIG-I signal pathways can trigger all kinds of programmed cell death However, unlike other cytosolic nucleic acid receptors (CGAs / sting) involved in ifn-1 release, the targeted activation of RIG-I in tumor cells has been proved to be an immunogenic variant of programmed cancer cell death (ICD), thus inhibiting the growth of a series of previously established tumor entities However, the molecular mechanism of driving the ig-i-induced ICD is still unclear, but it seems to involve the activation of only BH3 – only protein and caspase-3 Picture from science immunology, 2019, DOI: 10.1126/sciimmunologol.aau8943 It is not clear to what extent the signal of nucleic acid receptor in tumor affects the anti-tumor immune response mediated by ICB In view of the fact that the RIG-I / Mavs pathway is an important regulator of ifn-1 production and programmed cancer cell death, researchers from the University of technology in Munich, Germany, speculated that it may be involved in the treatment of ICB, and may be suitable for combined mode immunotherapy In a new study, the researchers confirmed that both anti-CTLA-4 immunotherapy and its combination with anti-PD-1 immunotherapy depend on the activation of the cytoplasmic RNA receptor, RIG-I, within tumor cells In terms of mechanism, tumor cells' intrinsic RIG-I signal induces caspase-3-mediated tumor cell death, CD103 + dendritic cells cross present tumor related antigens, and then tumor antigen-specific CD8 + T cell proliferation and accumulation of these T cells in tumor tissue The relevant research results were published in the Journal of science immunology on September 13, 2019 The title of the paper is "RIG-I activation is critical for responsiveness to checkpoint blockade" The therapeutic targeting of 5 '- triphosphate RNA to RIG-I in tumor and non malignant host cells can enhance the efficacy of CTLA-4 immunocheckpoint blocking in several preclinical cancer models In humans, transcriptome analysis of primary melanoma samples revealed a strong correlation between high expression of ddx58 (the gene encoding RIG-I), T cell receptor and antigen-presenting pathway activity, and prolonged overall survival Moreover, in melanoma patients receiving anti-CTLA-4 checkpoint blocking therapy, higher ddx58 RIG-I transcriptional activity was significantly associated with sustained clinical response In addition, melanoma cell lines lacking the key molecules involved in DNA and RNA detection, cell death and ifn-1 signaling pathways were designed by genetic methods These researchers classified the relative importance of these pathways in regulating the antitumor immune response and blocking the immune checkpoint Thus, these data confirm that the activation of RIG-I signal in tumor and its microenvironment is a key component of cancer immunotherapy mediated by immunocheckpoint inhibitors They also suggest that activation of the ability to sense (or detect) cytoplasmic RNA may be used to increase the immunogenicity of tumors with poor immunogenicity (BIOON Com) reference: Simon Heidegger et al RIG-I activation is critical for responsiveness to checkpoint blockade Science immunology, 2019, DOI: 10.1126/sciimmunologol.aau8943