In Vivo Visualizing the IFN-β Response Required for Tumor Growth Control in a Therapeutic Model of Polyadenylic-Polyuridylic Acid Administration

Abstract

The crucial role that endogenously produced IFN-β plays in eliciting an immune response against cancer has recently started to be elucidated. Endogenous IFN-β has an important role in immune surveillance and control of tumor development. Accordingly, the role of TLR agonists as cancer therapeutic agents is being revisited via the strategy of intra/peritumoral injection with the idea of stimulating the production of endogenous type I IFN inside the tumor. Polyadenylic-polyuridylic acid (poly A:U) is a dsRNA mimetic explored empirically in cancer immunotherapy a long time ago with little knowledge regarding its mechanisms of action. In this work, we have in vivo visualized the IFN-β required for the antitumor immune response elicited in a therapeutic model of poly A:U administration. In this study, we have identified the role of host type I IFNs, cell populations that are sources of IFN-β in the tumor microenvironment, and other host requirements for tumor control in this model. One single peritumoral dose of poly A:U was sufficient to induce IFN-β, readily visualized in vivo. IFN-β production relied mainly on the activation of the transcription factor IFN regulatory factor 3 and the molecule UNC93B1, indicating that TLR3 is required for recognizing poly A:U. CD11c+ cells were an important, but not the only source of IFN-β. Host type I IFN signaling was absolutely required for the reduced tumor growth, prolonged mice survival, and the strong antitumor-specific immune response elicited upon poly A:U administration. These findings add new perspectives to the use of IFN-β–inducing compounds in tumor therapy.

Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy

“…Studies that can obtain deeper mechanistic insights are surely needed to clarify this dual requirement. For example, using a therapeutic model of systemic poly A:U application, Nocera and colleagues have visualized IFN-β in the tumor microenvironment, identifying the CD11c + population as the main host source of IFN-β, but not the only one [ 362 ]. In this model, host type I IFN signaling was absolutely required for therapeutic efficacy and for poly A:U induced antitumor immunity.…”

TLR3 Activation of Intratumoral CD103+ Dendritic Cells Modifies the Tumor Infiltrate Conferring Anti-tumor Immunity

“…Polyadenylic-polyuridylic acid (poly A:U) is a double-stranded RNA mimetic that was used empirically in cancer immunotherapy in the early 80's with promising results and non-reported toxic effects (11–14). Interestingly, when naked poly A:U is administered locally at the tumor site, it inhibits tumor growth and prolongs survival in several murine cancer models (15). These important anti-tumor effects rely on type I interferon signaling on the host, since they are completely abolished in IFNAR1 −/− mice.…”

“…injection. The intratumoral source of the IFNβ required for the efficacy of the poly A:U treatment is a myeloid population within the tumor, carrying the CD11c and LysM markers (15). Interestingly, poly A:U mainly engages TLR3 and no other cytosolic receptors since the production of IFNβ at the tumor site is completely abolished in mice deficient for UNC93B1 signaling, a molecular chaperone strictly required for the activity of nucleic acid sensors, including TLR3 (15, 16).…”

“…The intratumoral source of the IFNβ required for the efficacy of the poly A:U treatment is a myeloid population within the tumor, carrying the CD11c and LysM markers (15). Interestingly, poly A:U mainly engages TLR3 and no other cytosolic receptors since the production of IFNβ at the tumor site is completely abolished in mice deficient for UNC93B1 signaling, a molecular chaperone strictly required for the activity of nucleic acid sensors, including TLR3 (15, 16). In this work, we used mice heterozygous for the Tlr3-EGFP allele (also known as B6- Tlr3 tm 2 Ciphe and called TLR3-GFP knock-in mice here) to identify TLR3 + cells within the tumor that therefore represent potentially the main targets of poly A:U and consequently, the putative source of IFNβ inside the tumor.…”

TLR3-Induced Maturation of Murine Dendritic Cells Regulates CTL Responses by Modulating PD-L1 Trafficking

“…Interestingly, administration of polyI:C at the same time as the antigen leads to a potent adaptive immune response whereas pre-sensitization with TLR3 ligands leads to inefficient immune responses [13–18]. The timing and route of the administration of polyI:C seems to impact on the efficiency of the CTL response induced [19, 20]. Furthermore, polyI:C has been notoriously shown to induce the expression of PD-L1, a widely expressed cell surface molecule that inhibits T cell responses through PD-1 [15].…”