G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells

Abstract

G-quadruplexes (G4s) are non-canonical nucleic acid structures involved in fundamental biological processes. As G4s are promising anticancer targets, in past decades the search for effective anticancer G4 binders aimed at the discovery of more cytotoxic ligands interfering with specific G4 structures at oncogenes or telomeres. Here, we have instead observed a significant activation of innate immune genes by two unrelated ligands at non-cytotoxic concentrations. The studied G4 binders (pyridostatin and PhenDC3) can induce an increase of micronuclei triggering the activation of the cytoplasmic STING (stimulator of interferon response cGAMP interactor 1) signaling pathway in human and murine cancer cells. Ligand activity can then lead to type I interferon production and innate immune gene activation. Moreover, specific gene expression patterns mediated by a G4 binder in cancer cells correlate with immunological hot features and better survival in human TCGA (The Cancer Genome Atlas) breast tumors. The findings open to the development of cytostatic G4 binders as effective immunomodulators for combination immunotherapies in unresponsive tumors.

Telomere as a Therapeutic Target in Dedifferentiated Liposarcoma

“…In particular, DDLPS cells exposed to an equitoxic concentration of RHPS4 were characterized by a marked accumulation of micronuclei, which exhibited extensive DNA damage in a significant proportion, as suggested by the positive staining for the phosphorylated form on Ser139 of histone H2AX [ 41 ]. Notably, this evidence corroborates the notion that micronuclei may form in the presence of dysfunctional telomeres [ 42 ], as well as recent findings showing that distinct G4 ligands may trigger the formation of micronuclei in different human tumor cells [ 43 , 44 , 45 ].…”

“…Notably, cGAS has been also found to localize at DNA bridges, which represent markers of telomere dysfunctions, thus raising the possibility that G4 binder-mediated dysfunctional telomeres may also play a role in innate immune signaling [ 42 ]. Noteworthily, enhanced micronuclei formation in breast cancer cells exposed to G4 binders has been recently reported to trigger the activation of innate immune genes (i.e., type I interferon genes) via cGAS-STING [ 44 ].…”

“…Strategies that enhance tumor immune infiltrate before treatment with immune checkpoint inhibitors may not only improve the response rate in tumors harboring an immune infiltrate but also increase immune infiltrate in non-responsive tumors, as shown in other solid neoplasms [ 52 , 53 ]. Hence, by favoring the accumulation of cytoplasmic DNA fragments directly or indirectly via oxidative stress [ 54 ], G4 binders may exert an immunomodulating activity that could be harnessed for an immunotherapy-based approach [ 44 , 54 ].…”

Combination of dl922-947 Oncolytic Adenovirus and G-Quadruplex Binders Uncovers Improved Antitumor Activity in Breast Cancer

“…Indeed, the dual role in cancer of this pathway is known since it can promote or inhibit tumorigeneses according to the biological context [ 38 ]. A previous study showed that STING pathway was induced by PDS in MCF-7 cells [ 39 ]. In agreement with this study, we observed that G4 ligands slightly increased STING expression and the effect was maintained with the virus and the combinatory treatments (although without reaching statistical significance).…”

Major Achievements in the Design of Quadruplex-Interactive Small Molecules

“…Moreover, G4 stabilizers such as pyridostatin and PhenDC3 (Figure 6) have also been shown to promote type I interferon production and innate immune gene activation, which could be helpful in combination immunotherapies for unresponsive tumors [105]. 2 and 3.…”