Rationale for stimulator of interferon genes-targeted cancer immunotherapy

Abstract

The efficacy of checkpoint inhibitor therapy illustrates that cancer immunotherapy, which aims to foster the host immune response against cancer to achieve durable anticancer responses, can be successfully implemented in a routine clinical practice. However, a substantial proportion of patients does not benefit from this treatment, underscoring the need to identify alternative strategies to defeat cancer. Despite the demonstration in the 1990's that the detection of danger signals, including the nucleic acids DNA and RNA, by dendritic cells (DCs) in a cancer setting is essential for eliciting host defence, the molecular sensors responsible for recognising these danger signals and eliciting anticancer immune responses remain incompletely characterised, possibly explaining the disappointing results obtained so far upon the clinical implementation of DC-based cancer vaccines. In 2008, STING (stimulator of interferon genes), was identified as a protein that is indispensable for the recognition of cytosolic DNA. The central role of STING in controlling anticancer immune responses was exemplified by observations that spontaneous and radiation-induced adaptive anticancer immunity was reduced in the absence of STING, illustrating the potential of STING-targeting for cancer immunotherapy. Here, we will discuss the relevance of manipulating the STING signalling pathway for cancer treatment and integrating STING-targeting based strategies into combinatorial therapies to obtain long-lasting anticancer immune responses.

Keywords: Adaptive immunity; Anticancer therapies; Cancer immunotherapy; DNA; Danger signal; Innate immunity; STING.

Figure 1

Involvement of STING in the promotion of tumor growth A) The stimulation of the STING signaling pathway by DNA elicits IDO dependent inhibition of effector T cells while promoting regulatory T cell activity resulting in enhanced tumor growth(–40). B) The leakage of DNA induced by 7,12-dimethylbenz[α]anthracene(DMBA), a potent carcinogen, can result in intrinsic chronic activation of STING signaling which drives phagocyte recruitment inflammation and tumor growth(41).

Figure 2

STING-driven cytokine secretion can activate adaptive immunity and prevent tumor growth A) Tumor derived-DNA recognition by STING, leads to IFNα/β secretion by CD8α⁺ DC, increased cross-priming and T cell activation(44) B) DNA damage induced by carcinogens, such as azoxymethane (AOM) or dextran sulfate sodium (DSS), triggers activation of the STING signaling pathway, resulting in IL-18 and IL-1β cytokine expression and favoring wound repair and tumor growth control(59).

Figure 3

Cell-intrinsic effect of STING activation in tumor cells The functionality of the STING signaling pathway can be altered in tumors. A) Oncolytic viruses like HPV or adenoviruses drive E7 or E1A oncoprotein expression. These proteins act as STING antagonists able to inhibit the STING pathway, possibly leading to their evasion from immune cells(62) B) Spontaneous epigenetic silencing of STING signaling components is also observed in various cancer types(63) C) Tumor DNA damage leads to Natural Killer cell activation through STING-dependent expression of RAE1(64). D) MUS81 endonuclease induces genomic DNA cleavage and accumulation followed by STING, type I IFN and CD8 T cell dependent rejection of tumor cells(66)

Figure 4

Therapeutic strategies combining STING targeting with immunomodulation and anticancer therapies The addition of STING agonists was shown to enhance the anticancer activity of the following anticancer therapies and immunomodulation strategies that elicit CD8 T cell dependent anticancer responses: A) Vaccination using Tumor Associated Antigen expressing attenuated Listeria Monocytogenes(77) B) Vaccination using Trivax (anti-CD40 as a co-stimulation signal, Poly(I:C) as adjuvant and peptide mix)(78) C) Radiotherapy(50) D) Chemotherapy, such as 5-Fluorouracil(82) E) Checkpoint inhibitors, such as anti-PD1(88) F) Vaccination using irradiated GM-CSF secreting tumor cells(88)