Intratumoral delivery of RIG-I agonist SLR14 induces robust antitumor responses.

Xiaodong Jiang,Anna Marie Pyle,Akiko Iwasaki,Marcus Bosenberg,Viswanathan Muthusamy,Yong Kong,Olga Fedorova,Daniel J Kim

doi:10.1084/jem.20190801

Xiaodong Jiang, Anna Marie Pyle + Show 6 more

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https://doi.org/10.1084/jem.20190801

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Abstract

Cytosolic nucleic acid-sensing pathways can be triggered to enhance immune response to cancer. In this study, we tested the antitumor activity of a unique RIG-I agonist, stem loop RNA (SLR) 14. In the immunogenic tumor models, we observed significant tumor growth delay and an extended survival in SLR14-treated mice. SLR14 also greatly improved antitumor efficacy of anti-PD1 antibody over single-agent treatment. SLR14 was mainly taken up by CD11b+ myeloid cells in the tumor microenvironment, and many genes associated with immune defense were significantly up-regulated after treatment, accompanied by increase in the number of CD8+ T lymphocytes, NK cells, and CD11b+ cells in SLR14-treated tumors. Strikingly, SLR14 dramatically inhibited nonimmunogenic B16 tumor growth, and the cured mice developed an immune memory. Furthermore, a systemic antitumor response was observed in both bilateral and tumor metastasis models. Collectively, our results demonstrate that SLR14 is a promising therapeutic RIG-I agonist for cancer treatment, either alone or in combination with existing immunotherapies.

Highlights

The innate immune system relies on pattern recognition receptors (PRRs) to sense invading microbes to initiate a rapid protective response
Combination treatment with SLR14 and anti-PD1 leads to better antitumor effects than single treatment As YMR1.7 clearance depends on T cells and is sensitive to immune checkpoint inhibitors including anti-CTLA4 and anti-PD1 (Wang et al, 2017b), we examined if SLR14 and anti-PD1 combined treatment might improve the antitumor efficacy of single treatment
Our results showed that ∼21.9% of CD11b+ cells in draining lymph node (dLN) had taken up SLR14, while no SLR14+CD11b+ cells were detected in nondraining lymph node (ndLN) (Fig. 3 B)

Summary

Introduction

The innate immune system relies on pattern recognition receptors (PRRs) to sense invading microbes to initiate a rapid protective response. The PRRs sensing microbial NAs are crucial for antimicrobial defense (Hlavata et al, 2018) These NA–sensing PRRs include (1) the endosomal TLR family (Majer et al, 2017); (2) the cytosolic DNA sensors cyclic GMP-AMP synthetase (cGAS) and AIM2 (Chen et al, 2016b); and (3) the cytosolic RNA sensors retinoic acid–inducible gene I (RIG-I)–like receptor family (Schlee, 2013). Once activated, these NA–sensing PRRs trigger multiple signaling cascades to induce the production of type I IFNs and proinflammatory cytokines, serving as the first line of defense against viral and microbial infections (Iwasaki and Medzhitov, 2010). Recent studies revealed that dying or damaged cancer cells could release NAs that can be recognized by cytosolic PRRs to induce antitumor immune response (Flood et al, 2019)

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