Activating the Nucleic Acid-Sensing Machinery for Anticancer Immunity

Abstract

Nucleic acid sensing pathways have likely evolved as part of a broad pathogen sensing strategy intended to discriminate infectious agents and initiate appropriate innate and adaptive controls. However, in the absence of infectious agents, nucleic acid sensing pathways have been shown to play positive and negative roles in regulating tumorigenesis, tumor progression and metastatic spread. Understanding the normal biology behind these pathways and how they are regulated in malignant cells and in the tumor immune environment can help us devise strategies to exploit nucleic acid sensing to manipulate anti-cancer immunity.

Keywords: Cancer; Innate immunity; RIG-I; STING; TLR; Tumor; Vaccine.

Figure 1.

Nucleic acid sensing mechanisms are dominantly located inside cells and consistently signal the presence of nucleic acids through activation and nuclear translocation of IRF3.

Figure 2.

The tumor can contain a heterogenious cell population including cancer cells and immune cell types that can respond to nucleic acids. Nucleic acid sensing in cancer cells can result in inflammatory cytokine secretion to the microenvironment, or cancer cell material can be transfered to the neighboring immune cells, which can themselves sense nucleic acids and secrete inflammatory cytokines. Alternatively, exogenous administration of agents that activate nucleic acids can result in activation of multiple cell types in the tumor environment.

Figure 3.

Necrosis is a common feature in advanced cancers, due to aggressive growth of cancer cells outstripping the vascular supply. Necrosis can supply endogenous nucleic acids to surrounding immune cells. In addition, nucleic acids can be provided by apoptotic bodies, exosomes, or detected endogenously via micronuclei or autophagosomes.

Figure 4.

Following radiation therapy, tumor associated antigens can be released to antigen-presenting cells that can travel to draining lymphatics and activate antigen-specific T cells. Activation of nucleic acid sensors can improve the fuction of antigen-presenting cells, permitting increased T cell expansion and improved recruitment of T cells to the draining lymphatics and back to the tumor via inflamed endothelia. Increased antigen specific T cells in the peripheral circulation can also travel to distant, untreated tumors, but their recruitment will be limited by poorly inflamed vasculature and ongoing negative regulation in the untreated site.