Targeting Cytosolic Nucleic Acid-Sensing Pathways for Cancer Immunotherapies

Abstract

The innate immune system provides the first line of defense against pathogen infection though also influences pathways involved in cancer immunosurveillance. The innate immune system relies on a limited set of germ line-encoded sensors termed pattern recognition receptors (PRRs), signaling proteins and immune response factors. Cytosolic receptors mediate recognition of danger damage-associated molecular patterns (DAMPs) signals. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Recent studies revealed that PRRs respond to nucleic acids (NA) released by dying, damaged, cancer cells, as danger DAMPs signals, and presence of signaling proteins across cancer types suggests that these signaling mechanisms may be involved in cancer biology. DAMPs play important roles in shaping adaptive immune responses through the activation of innate immune cells and immunological response to danger DAMPs signals is crucial for the host response to cancer and tumor rejection. Furthermore, PRRs mediate the response to NA in several vaccination strategies, including DNA immunization. As route of double-strand DNA intracellular entry, DNA immunization leads to expression of key components of cytosolic NA-sensing pathways. The involvement of NA-sensing mechanisms in the antitumor response makes these pathways attractive drug targets. Natural and synthetic agonists of NA-sensing pathways can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment and are being explored as promising adjuvants in cancer immunotherapies. In this minireview, we discuss how cGAS–STING and RIG-I–MAVS pathways have been targeted for cancer treatment in preclinical translational researches. In addition, we present a targeted selection of recent clinical trials employing agonists of cytosolic NA-sensing pathways showing how these pathways are currently being targeted for clinical application in oncology.

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

“…Small molecule STING agonists elicit potent pro-inflammatory responses, and correspondingly have shown significant efficacy as cancer immunotherapies 24,25 .…”

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…8,[10][11][12][13][14][15][16][17][18][19][20][21] Based on a series of fundamental studies, preclinical validations and clinical biomarker assessments [22][23][24] ICD can be defined as a functionally unique RCD subtype that is sufficient for the elicitation of adaptive immunity specifically directed toward antigens derived from cell "corpses". 4, 9,12,15,21,[25][26][27][28][29][30][31][32][33][34][35][36] It is now well acknowledged that, upon antigenic priming coupled to the emission of damage-associated molecular patterns (DAMPs) and immunostimulatory cytokines, 8,9,12,15,[19][20][21][27][28][29]31,[36][37][38][39][40]…”

Type I interferons and endoplasmic reticulum stress in health and disease

“…Danger signaling is a context-dependent inflammatory process, that can aid or impede canonical inflammatory reactions, depending upon the type of DAMPs emitted and cognate receptors engaged, thereby either ameliorating or exacerbating a particular disease (de Haan et al, 2013;Brenner et al, 2013;Foell et al, 2007;Garg and Agostinis, 2017;Garg et al, 2016a;O'Shea and Murray, 2008;Rock and Kono, 2008). For instance, in case of diseases with dysregulated inflammatory milieu (e.g., cancer), ordered exposure of prophagocytic, chemotactic and immune cell activating DAMPs can be crucial for induction of anticancer immunity (Bracci et al, 2017;Cronin and Penninger, 2007;Fang et al, 2019;Galluzzi et al, 2017;He et al, 2013;Iurescia et al, 2018;Lee et al, 2016;Ma et al, 2011;Ravichandran, 2011;Seong and Matzinger, 2004). In contrast, DAMPs can not only support autoimmune diseases (e.g., GRP78 in case of autoimmune diabetes) but, they can also sometime be the primary pathological factors underlying their progression (e.g., nucleic acids during lupus) (Anaya et al, 2007;Anders, 2005;Cheng and Anderson, 2012;Cunha-Neto et al, 2011;Pedersen et al, 2011;Rizzo et al, 2014;Rondas et al, 2015).…”

“…Lastly, major cytosolic PRRs crucial for type I IFN induction include, cytosolic cGAMP-AMP synthase (cGAS)/absent in melanoma 2 (AIM2)-like receptors (ALRs) or, melanoma differentiationassociated gene 5 (MDA5)/RNA helicases retinoic acid-inducible gene I (RIG-I), that are frequently engaged by danger signals like cytosolic DNA species or microbial RNA species (e.g., dsRNA or 5 0 ppp-RNA), respectively ( Fig. 1) (Elion and Cook, 2018;Iurescia et al, 2018;Lee et al, 2019;Saito and Gale, 2008;Tan et al, 2018;Vanpouille-Box et al, 2018).…”