RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade

Heidegger, Simon; Kreppel, Diana; Bscheider, Michael; Stritzke, Florian; Nedelko, Tatiana; Wintges, Alexander; Bek, Sarah; Fischer, Julius; Graalmann, Theresa; Kalinke, Ulrich; Bassermann, Florian; Haas, Tobias; Poeck, Hendrik

doi:10.1016/j.ebiom.2019.02.056

Cited by 33 publications

(44 citation statements)

References 41 publications

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“…Recent research found that protein vaccination together with RIG‐I ligation via 3pRNA strongly synergized with CTLA‐4 blockade could induce expansion and activation of antigen‐specific CD8 + T cells. [ 168 ] Taken together, the combination of IFN‐Is therapy and ICB therapy is better than any of them alone.…”

Section: Application Of Ifn‐is In Tumor Therapymentioning

confidence: 99%

A Dual Role of Type I Interferons in Antitumor Immunity

et al. 2020

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activation, cell growth, and apoptosis. [2] IFNs can be classified into type I, type II, and type III IFNs according to their chromosomal localization and receptor specificity. IFN-Is include 17 different proteins composed of IFN-β, IFNε, IFNκ, IFNω, and 13 subtypes of IFNα. These genes are all located on the short arm of chromosome 9, of which IFNα and IFN-β play a crucial role in innate and adaptive immunity against viruses. [3] Type II IFN family has a sole member IFN-γ, and locates on chromosome 12. [4] It is mainly produced by T cells and has a key role in adaptive immunity. [4] Type III IFNs is a new family of IFNs, consisting of four members, IFN-λ1,-λ2,-λ3, and-λ4. All these genes are closely positioned on chromosome 19. [5] IFN-λs also have antiviral activity and they are key determinants of innate immunity at mucosal sites. [5] Although initially described for their antiviral functions, all types of IFNs have been shown considerable potency in promoting antitumor functions in vivo. [5,6] In 1967 Gresser et al. first reported that the repeated administration of interferon preparations delayed the evolution of friend leukemia in mice; [7] and in the next year he got the similar results in Rauscher leukemia. [8] Later on, they found murine interferon preparations significant prolonged the survival of the mice implanted with viral particles-presented tumor cells. [9] IFN-Is were then purified and used in clinical trials and the subsequent results further confirmed their sustained antitumor effects in a diversity of hematological malignancies and metastatic solid tumors. [10] Moreover, recombinant IFNα2 became the first human immunotherapeutic approved by the US Food and Drug Administration (FDA) for cancer. [11] However, recent findings suggested that IFN-Is also played a negative role in antitumor immunity. Prolonged IFN-I signaling could lead to immune dysfunction and cause adaptive resistance. [6] Therefore, it is important to know the appropriate conditions that IFN-Is could be used in clinical to avoid unwanted consequences. In this review, we focus on the dual functions of IFN-Is on antitumor immune responses and discuss in detail the underlying mechanisms. 2. IFN-Is Production and Transduction IFN-Is are induced following activation of pattern recognition receptors (PRRs), including retinoic-acid-inducible Type I interferons (IFN-Is) are a family of cytokines that exert direct antiviral effects and regulate innate and adaptive immune responses through direct and indirect mechanisms. It is generally believed that IFN-Is repress tumor development via restricting tumor proliferation and inducing antitumor immune responses. However, recent emerging evidence suggests that IFN-Is play a dual role in antitumor immunity. That is, in the early stage of tumorigenesis, IFN-Is promote the antitumor immune response by enhancing antigen presentation in antigen-presenting cells and activating CD8 + T cells. However, in the late stage of tumor progression, persistent expression of IFN-Is induces the expression of im...

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Section: Application Of Ifn‐is In Tumor Therapymentioning

confidence: 99%

A Dual Role of Type I Interferons in Antitumor Immunity

et al. 2020

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“…82 Accordingly, 5′ppp-RNA treatment could sensitive ICIs treatment in vivo. [82][83][84] In primary human melanoma tissues, high expression of RIG-I was associated with T cell receptor and antigen presentation pathway activation, the prolonged overall survival of patients, and durable clinical responses to anti-CTLA-4 checkpoint blockade. 85 Thus, the high expression of RIG-I in cancer cells may indicate a better response to immune checkpoint blockade which still needs further research.…”

Section: The Combination Of Nuclei Acid-sensing Immunity With Icis Asmentioning

confidence: 99%

Targeting nuclear acid-mediated immunity in cancer immune checkpoint inhibitor therapies

Chen

et al. 2020

Sig Transduct Target Ther

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Cancer immunotherapy especially immune checkpoint inhibition has achieved unprecedented successes in cancer treatment. However, there are many patients who failed to benefit from these therapies, highlighting the need for new combinations to increase the clinical efficacy of immune checkpoint inhibitors. In this review, we summarized the latest discoveries on the combination of nucleic acid-sensing immunity and immune checkpoint inhibitors in cancer immunotherapy. Given the critical role of nuclear acid-mediated immunity in maintaining the activation of T cell function, it seems that harnessing the nuclear acid-mediated immunity opens up new strategies to enhance the effect of immune checkpoint inhibitors for tumor control.

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“…Upon activation, these sensors promote antigen presentation, a type-1 interferon response, pyroptosis, DAMPs secretion, and immunogenic cell death ( 25 ). Recently, RLR activation was found to boost the efficiency of anticancer vaccines and to be critical for responsiveness to immune checkpoint blockade ( 26 , 27 ).…”

Section: Introductionmentioning

confidence: 99%

“…This is done using a delivery agent, such as the cationic polymer polyethylenimine (PEI), which masks the viral dsRNA until it reaches the cytoplasm, where it is released and recognized ( 29 , 30 ). PolyIC cytoplasmic delivery was previously tested as a targeted therapy ( 26 , 31 ), a systemic therapy ( 32 , 33 ), and a local therapy ( 34 ). However, the effects of this treatment on distant metastases or in combination with radiotherapy have not been well-investigated.…”

Section: Introductionmentioning

confidence: 99%

RIG-1-Like Receptor Activation Synergizes With Intratumoral Alpha Radiation to Induce Pancreatic Tumor Rejection, Triple-Negative Breast Metastases Clearance, and Antitumor Immune Memory in Mice

et al. 2020

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Diffusing alpha-emitting radiation therapy (DaRT) employs intratumoral Ra-224-coated seeds that efficiently destroy solid tumors by slowly releasing alpha-emitting atoms inside the tumor. In immunogenic tumor models, DaRT was shown to activate systemic antitumor immunity. Agonists of the membrane-bound toll-like receptors (TLRs) enhanced these effects and led to tumor rejection. Here, we examined the combination of DaRT with agents that activate a different type of pattern recognition receptors, the cytoplasmatic RIG1-like receptors (RLRs). In response to cytoplasmatic viral dsRNA, RLRs activate an antiviral immune response that includes the elevation of antigen presentation. Thus, it was postulated that in low-immunogenic tumor models, RLR activation in tumor cells prior to the induction of their death by DaRT will be superior compared to TLR activation. Intratumoral cytoplasmatic delivery of the dsRNA mimic polyIC by polyethylenimine (PEI), was used to activate RLR, while polyIC without PEI was used to activate TLR. PolyIC(PEI) prior to DaRT synergistically retarded 4T1 triple-negative breast tumors and metastasis development more efficiently than polyIC and rejected panc02 pancreatic tumors in some of the treated mice. Splenocytes from treated mice, adoptively transferred to naive mice in combination with 4T1 tumor cells, delayed tumor development compared to naïve splenocytes. Low-dose cyclophosphamide, known to reduce T regulatory cell number, enhanced the effect of DaRT and polyIC(PEI) and led to high long-term survival rates under neoadjuvant settings, which confirmed metastasis clearance. The epigenetic drug decitabine, known to activate RLR in low doses, was given intraperitoneally prior to DaRT and caused tumor growth retardation, similar to local polyIC(PEI). The systemic and/or local administration of RLR activators was also tested in the squamous cell carcinoma (SCC) tumor model SQ2, in which a delay in tumor re-challenge development was demonstrated. We conclude that RIG-I-like activation prior to intratumoral alpha radiation may serve as a potent combination technique to reduce both tumor growth and the spread of distant metastases in low-immunogenic and metastatic tumor models.

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RIG-I activating immunostimulatory RNA boosts the efficacy of anticancer vaccines and synergizes with immune checkpoint blockade

Cited by 33 publications

References 41 publications

A Dual Role of Type I Interferons in Antitumor Immunity

A Dual Role of Type I Interferons in Antitumor Immunity

Targeting nuclear acid-mediated immunity in cancer immune checkpoint inhibitor therapies

RIG-1-Like Receptor Activation Synergizes With Intratumoral Alpha Radiation to Induce Pancreatic Tumor Rejection, Triple-Negative Breast Metastases Clearance, and Antitumor Immune Memory in Mice

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