Chapter Six - Activating the Nucleic Acid-Sensing Machinery for Anticancer Immunity

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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.

Introduction

Cancer arises from dysregulated expansion of our own cells due to an accumulation of gene mutations that divert cells from their normal function. The progressive nature of tumorigenesis means that at various points, cancer cells have an array of mutations but are not yet malignant, and the final malignant clone may arise out of a premalignant state that may have been present for a prolonged period of time (Fearon and Vogelstein, 1990). Recently, with the rapid acceptance of immunotherapy, we have seen clinical validation of the power of the immune system to recognize and control tumors via targeting of mutated genes as antigenic targets (Tran et al., 2017). As an example, these antigenic targets can include mutated K-ras (Tran et al., 2016), which is considered an early common mutation in tumorigenesis (Fearon and Vogelstein, 1990). In this case, these data imply that there is an extended interaction between mutated cancer cells and a host immune system that has the capacity to recognize these mutations as antigens, yet cancer continues to progress and acquire further mutations until it develops into symptomatic disease.

This disconnect between the capacity of the immune system to recognize antigens and whether they actually do so is well known in immunology. Antigens are not sufficient to initiate immune responses. Immunology is all about the involvement of the right cells, in the right places, with the right signals to support immunity. While we continue to discover novel immune regulatory molecules, pathways and cells, certain features remain true. One truism is the core principle of antigen plus adjuvant being critical to initiate immune responses. This principal explains why systemic application of antigenic peptides alone results in antigen specific tolerance and eventual deletion of antigen specific T cells (Liblau et al., 1996). However, systemic application of a virus expressing this antigenic peptide or the peptide pulsed on an activated dendritic cell results in powerful antigen-specific responses. The difference lies in the context in which the antigen-specific T cells see their antigens, which is dominated by the influences of the cells that present the antigen, the adjuvant signals that influence the context of antigen presentation and the specific molecular interactions between antigen presenting cells and T cells. The role of nucleic acids in activating the immune system has been of interest to scientists ever since Isaacs et al. discovered that mouse cells infected with chicken nucleic acids produced interferons (Isaacs et al., 1963). As we will discuss, it is in this context that nucleic acid sensing mechanisms play a critical role in vaccination-based strategies to engender anti-cancer immunity.

In view of the capacity of immune cells to recognize and destroy cancer cells, it is now recognized that negative regulation of immune responses is a critical feature that allows mutated cells to develop into advanced malignancies (Hanahan and Weinberg, 2011). This requirement to suppress or control anti-cancer immunity is in addition to the positive role that inflammation can provide in driving tumorigenesis through constant remodeling of the epithelium (DeNardo et al., 2010). As we will discuss, nucleic acid sensors have been shown to influence tumorigenicity in animal models in part by regulating tumorigenic inflammation. These mechanisms remain influential throughout malignant progression, and as we will discuss, there are a range of autophagic and cell-death related processes that result in activation of nucleic acid sensors that activate inflammatory mechanisms to continuously remodel the tumor immune environment. However, the majority of the studies on nucleic acid sensing and cancer have focused on treatment of advanced malignancies. Here there are two dominant approaches. In the first, exogenous ligands for nucleic acid sensors are applied to tumors to activate inflammatory pathways in the tumor environment. In the second, treatments such as chemotherapy and radiation therapy influence endogenous nucleic acid processing mechanisms to activate nucleic acid sensors in the tumor environment. We will discuss the current status of each of these interventions and how they likely impact control of tumors by immune mechanisms. A list of abbreviations used in this review is provided in Table 1.

Section snippets

Overview of Nucleic Acid Sensors

Nucleic acid sensing can be viewed as a subset of innate mechanisms to detect viral and bacterial infection. The prototypic innate sensors are the Toll-like receptors (TLRs) (Medzhitov et al., 1997), a hugely influential family of molecules that activate inflammatory mechanisms in response to a wide variety of targets, from lipopolysaccharide (TLR4) to unmethylated CpG dinucleotides (TLR9) (reviewed in Iwasaki and Medzhitov (2004); Yin et al. (2015)). In general, TLRs share a common cytoplasmic

DNA Sensing in Tumorigenesis Versus Treatment

Cells of the immune system, as well as epithelial cells that come in contact with invading pathogens have evolved these nucleic acid sensing mechanisms to combat foreign material present or mislocalized within cells. As discussed, pathogen-associated molecular pattern receptors and damage-associated molecular pattern receptors expressed by these cell types include STING, TLRs, RIG-I-like receptors, HMGB1, DDX41, IFI16, IFI204, DAI, and components of the inflammasome (e.g., NLRs and AIM2) that

Exogenous Activation by Administration of Ligands

Given that the aforementioned studies demonstrate that nucleic acid sensing within tumors generally acts as a tumor suppressor, emerging studies are exploiting these pathways for their therapeutic potential. Synthetic cyclic dinucleotides have recently been developed for preclinical and clinical use as potent modulators of STING for anticancer therapy. Use of these agonists has been used successfully to induce tumor regression in preclinical models of pancreatic cancer (Baird et al., 2016),

Endogenous Nucleic Acid Sensor Activation by Host Ligands

In view of our limited ability to develop cancer vaccines that apply to many different patients due to the great variation in antigenic mutations between people, an alternative approach is to use the patients own tumor as the nexus to initiate anti-tumor immunity (Crittenden et al., 2005). As discussed above, initial immune recognition of infection is often triggered through the recognition of conserved microbial patterns including those based on nucleic acids.

Of course, under normal conditions

Does Cancer Have a Particular Tendency to Activate Nucleic Acid Sensors?

Since cancer cells fit into a number of the categories described above that can result in endogenous activation of nucleic acid sensors, and there is evidence that these sensors can regulate tumorigenesis and progression, it begs the question as to whether these sensors are constantly active in cancer cells. However, in addition to cell-intrinsic nuclear material, cancer can have an abundant supply of extrinsic nuclear material, since areas of necrosis are frequently detectable in growing

Role of DNA Damaging Agents in Cancer Treatment

As discussed above, there is an abundance of data indicating that delivering agents that activate nucleic acid sensors in tumors can activate anti-cancer immunity in part by triggering nucleic acid sensing mechanisms within damaged cells. In view of these data, it would suggest that nucleic acid sensing mechanisms may contribute to immune activation following conventional cytotoxic therapies. Recent data suggest that this may be true (Harding et al., 2017; Vanpouille-Box et al., 2017).

Conclusions

Nucleic acid sensors represent a particularly potent group of molecular pathways capable of initiating anti-bacterial and anti-viral immunity both via innate mechanisms as well as via induction of cell-mediated immunity. These pathways can also play a role in tumorigenesis, but triggering these pathways in advanced cancers can generate protective anti-tumor immune responses. There is a long history of combining innate adjuvants as part of anti-cancer vaccines (reviewed in Coffman et al. (2010);

Funding

This work was funded by NCI R01CA182311 (MJG), and an American Cancer Society Postdoctoral Fellowship award (J.R.B.).

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